Substituted benzodioxane, benzodioxole and benzodioxepine compounds

ABSTRACT

Alcohol, thiol, epoxylated alcohol, epoxylated thiol and benzyloxy derivatives of benzodioxane, benzodioxole and benzodioxepine are useful as intermediates for preparing certain useful cinnamoyl piperazines and homopiperazines.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of Ser. No. 894,965, filedApr. 10, 1978 now U.S. Pat. No. 4,178,442.

This invention relates to compounds having the formula: ##STR1##wherein: I. R is ##STR2## and the parameters (X,n) are: A. (oxygen, 2)and R₉ is methoxy, acetoxy, methyl, cyano, acetyl, n-butyroyl,alkoxycarbonyl in which the alkyl group is linear or branched and hasfrom 2 to 5 carbon atoms, cyclohexyloxycarbonyl, carboxamido,N-methylcarboxamido, N-cyclohexylcarboxamido, N-phenylcarboxamido,alkanoylamino in which the alkyl group is linear or branched and has 1to 4 carbon atoms, cyclohexylcarbonylamino, benzoylamino,N-alkylcarbamoylamino in which the alkyl group is linear or branched andhas from 1 to 5 carbon atoms, N-cyclohexylcarbamoylamino,N-phenylcarbamoylamino, N-(paramethoxyphenyl) carbamoylamino,N,N-dimethylcarbamoylamino, morpholinocarbonylamino, N,N'-dimethylcarbamoylamino, ethoxycarbonylamino, cyanomethyl, ethyl acetate,carboxamidomethyl or N-methylcarboxamidomethyl,

B. (oxygen, 1) or (oxygen, 3) and R₉ is acetyl, acetamido orN-methylcarbamoylamino,

C. (sulfur, 2) and R₉ is hydrogen or acetyl,

II. R is hydrogen and the parameters (X, n) are:

A. (oxygen, 2) and R₉ is acetoxy, cyano, methyl, n-butyroyl,alkoxycarbonyl in which the alkyl group is linear or branched and hasfrom 2 to 5 carbon atoms, cyclohexyloxycarbonyl, carboxamido,N-methylcarboxamido, N-cyclohexylcarboxamido, N-phenylcarboxamido,alkanoylamino the alkyl group is linear or branched and has from 1 to 5carbon atoms, cyclohexylcarbonylamino, benzoylamino,N-alkylcarbamoylamino the alkyl group of which is linear or branched andhas from 1 to 5 carbon atoms, N-cyclohexylcarbamoylamino,N-phenylcarbamoylamino, N-paramethoxyphenylcarbamoylamino,N,N-dimethylcarbamoylamino, morpholinocarbonylamino,N,N'-dimethylcarbamoylamino, ethoxycarbonylamino, hydroxymethyl,cyanomethyl, ethyl acetate, carboxamidomethyl andN-methylcarboxamidomethyl and acetyl oxime,

B. (oxygen, 1), (oxygen, 3) and R₉ is acetyl, acetamido orN-methylcarbamoylamino,

C. (sulfur, 2) and R₉ is hydrogen or acetyl,

III. R is ##STR3## and the parameters (X, n) are: A. (oxygen, 2) and R₉is methoxy, acetyl, hydroxy, acetoxy, alkoxycarbonyl in which the alkylgroup is linear or branched and has from 2 to 5 carbon atoms,cyclohexyloxycarbonyl, carboxamido, N-methylcarboxamido,N-cyclohexylcarboxamido, N-phenylcarboxamido, alkanoylamino the alkylgroup of which is linear or branched and has from 2 to 5 carbon atoms,cyclohexylcarbonylamino, benzoylamino, N-alkylcarbamoylamino the alkylgroup of which is linear or branched and has from 1 to 5 carbon atoms,N-cyclohexylcarbamoylamino, N-phenylcarbamoylamino,N-paramethoxyphenylcarbamoylamino, ethoxycarbonylamino,N,N'-dimethylcarbamoylamino, methylamino, morpholinocarbonylamino,N,N-dimethylcarbamoylamino, carboxamidomethyl,N-methylcarboxamidomethyl, hydroxycarbonylmethyl, cyano, ethyl acetate,carboxy, amino, hydroxymethyl, cyanomethyl, chloromethyl or acetamido,

B. (oxygen, 1) or (oxygen, 3) and R₉ is N-methylcarbamoylamino, acetyl,amino, acetamido or acetyloxime.

The compounds of the invention are useful as intermediates for preparinguseful compounds having the following formula (I), as disclosed in U.S.Pat. application Ser. No. 894,965, filed Apr. 10, 1978 now U.S. Pat. No.4,178,442, the entire contents of which are incorporated herein byreference. ##STR4## in which: ##STR5## represents the 3,4,5trimethoxyphenyl group ##STR6## in which case the set of parameters (n,R, X, m) takes: +either the value (1, OH, Oxygen, O), the radical ARthen representing:

-a mono or polysubstituted phenyl nucleus: ##STR7## in which R₂, R₃, R₄,R₅ and R₆ represent simultaneously the following values;

•R₃ =R₄ =R₅ =R₆ =H; R₂ then represents either the atom of chlorine orfluorine or the acetamido, acetyl, cyano, methoxy, methyl, allyl orallyloxy groups,

•R₂ =R₄ =R₅ =R₆ =H; R₃ represents the acetamido, methyl, acetyl, cyano,methoxy groups or the atom of chlorine,

•R₂ =R₃ =R₅ =R₆ =H; R₄ represents the atom of chlorine or the cyano,nitro, methylthio, benzoyl, ethyl carboxylate, methyl groups, linear orbranched alkyl possessing from 3 to 5 atoms of carbon, cyclohexyl,alkanoyl of which the alkyl has from 1 to 3 carbon atoms, alkanoylaminowhose alkyl comprises from 1 to 3 carbon atoms, carboxamido or N-methylcarboxamido, or the cyanomethyl, carboxamidomethyl orN-methylcarbamoylamino chains,

•R₃ =R₅ =R₆ H; R₂ represents the atom of fluorine and R₄ represents theacetyl group,

•R₃ =R₅ =R₆ H; R₂ represents the chlorine atom and R₄ represents eitherthe nitro or acetyl groups, or the N-methyl carbamoyl amino chain;

•R₃ =R₅ =R₆ =H; R₂ represents the methyl group and R₄ represents eitherthe chlorine atom or the acetyl or acetamido groups or the N-methylcarbamoyl amino chain,

•R₃ =R₅ =R₆ H; R₂ represents the methoxy group and R₄ represents theacetyl, propionyl, formyl, cyano, acetamido, or N-methyl carboxamidogroups,

•R₄ =R₅ =R₆ =H; R₂ and R₃ represent the methoxy group,

•R₃ =R₄ =R₅ =H; R₂ and R₆ represent the methoxy group,

•R₂ =R₄ =R₆ =H; R₃ and R₅ represent the methoxy group,

•R₂ =R₅ =R₆ =H; R₃ and R₄ represent together methylene dioxy,

•R₂ =R₅ =R₆ =H; R₃ represents the methyl group and R₄ represents thenitro, or acetamido groups or the N-methyl carbamoylamino chain,

•R₂ =R₆ =H; R₃, R₄ and R₅ represent the methoxy group,

•R₂ =R₆ =H; R₃ and R₅ represent the methyl group and R₄ represents thechlorine atom,

•R₅ =R₆ =H; R₂ and R₃ represent the methoxy group and R₄ the N-methylcarbamoyl amino group,

•R₃ =R₅ =H; R₂ and R₆ represent the chlorine atom and R₄ represents theacetyl group or the N-methyl carbamoyl amino chain,

•R₃ =R₅ =H; R₂ and R₆ represent the methoxy group and R₄ represents theacetyl, or ethyl carboxylate groups or the N-methyl carbamoyl aminochain,

•R₅ =H; R₃, R₄ and R₆ represent the methoxy group and R₂ represents theacetyl group,

-a heterocycle of formula ##STR8## in which p, R₇, R₈ and R₉ representsimultaneously the following values,

•p=2; R₇ =R₈ =H; R₉ represents either the hydrogen atom or the hydroxy,acetoxy, methoxy, methyl, ethyl, cyano, acetyl, n-butyroyl, alkoxycarbonyl in which the alkyl is linear or branched and comprises from 2to 5 carbon atoms, cyclohexyloxy carbonyl, carboxamido, N-methylcarboxamido, N-cyclohexyl carboxamido, N-phenyl-carboxamido groups,alkanoyl amino group whose linear or branched alkyl has from 1 to 5carbon atoms, cyclohexylcarbonylamino, benzoylamino,N-alkylcarbamoylamino whose linear or branched alkyl has from 1 to 5carbon atoms, N-cyclohexylcarbamoylamino, N-phenylcarbamoylamino,N-(paramethoxy phenyl)-carbamoylamino, N,N-dimethylcarbamoylamino,morpholinocarbonylamino, N,N'-dimethylcarbamoylamino, ethoxycarbonylamino groups or the hydroxymethyl, cyanomethyl, ethyl acetate,carboxamido methyl or N-methyl carboxamido methyl chains,

•p=2; R₇ =R₉ =H; R₈ represents the acetyl group,

•p=2; R₈ =R₉ =H; R₇ represents the acetamido group,

•p=1 or 3; R₇ =R₈ =H; R₉ represents either the hydrogen atom or theacetyl, acetamido or N-methylcarbamoyl amino groups,

-a naphthalene nucleus of the type ##STR9## in which R₁₀ represents theacetyl, acetamido or N-methyl carbamoyl amino groups,

-a heterocycle of formula ##STR10## in which q assumes the values 1 or 2and R₁₀ has the same meaning as previously,

-the groups (oxo-1, tetrahydro 1-2-3-4 naphtyl)-5 of formula ##STR11##and (oxo-1, tetrahydro 1-2-3-4 naphtyl)-6 of formula ##STR12## +or thevalue (2, OH, Oxygen, 0) the Ar radical then representing: -either thephenyl group,

-or an aromatic group ##STR13## in which R₁₁ represents the hydrogenatom or the methoxy group, -or a heterocycle ##STR14## in which R₁₀ hasthe same meaning as previously, +or the value (1, H, Oxygen, 0), the Arradical then representing a heterocycle of the type ##STR15## in which:R₁₂ represents the acetyl, acetamido, N-methyl carboxamido orN-methylcarbamoylamino groups,

+or the value (1, OH, S, 0), the Ar radical then representing:

-either the phenyl, meta-methoxyphenyl or paratolyl groups,

-or an aromatic group ##STR16## in which R₁₁ represents the hydrogenatom or the methoxy group, -or a heterocycle ##STR17## in which R₁₃represents the hydrogen atom or the acetyl group, +or the value##STR18## the Ar radical then representing the phenyl group, +or thevalue (1, OH, Oxygen, 1), the Ar radical then representing the phenylgroup, ##STR19## represents: +either the 4-fluorophenyl,3,5-dimethoxyphenyl or 3,4-methylenedioxyphenyl groups,

+or the aromatic groups ##STR20## in which R₁₄ represents the hydrogenatom or a linear or branched alkyl having 2 to 3 carbon atoms

in which case the set of parameters (n, R₁, X, m), assumes the value (1,OH, Oxygen, 0) and the Ar radical represents the ##STR21## group##STR22## represents the group ##STR23## in which case the set ofparameters (n, R₁, X, m) assumes the value (1, OH, Oxygen, 0) and Ar is##STR24##

The process for preparing the compounds of formula (I), except for the 7following compounds of formula (I):

•the compound of formula (I) in which ##STR25## •the compound of formula(I) in which X represents the methylamino group ##STR26## •the compoundof formula (I) in which Ar is ##STR27## and •the four compounds offormula (I) in which R₁ represents the hydrogen atom,

consists in condensing a piperazine or a homopiperazine of formula (II)##STR28## in which n assumes the values 1 and 2 and ##STR29## has thesame meanings as ##STR30## in formula (I) except for the value ##STR31##with an epoxy of formula (III): ##STR32## in which Ar' has the samemeaning as Ar in formula (I), except for the value ##STR33## and X'represents the atom of oxygen or sulphur, or with epoxy-2,3 benzyloxy-1propane, to obtain the compound of formula (I) in which m=1.

This condensation is carried out preferably in ethanol with reflux.

Following the same process as above, but from suitable reagents, thecompound corresponding to formula (Ia): ##STR34## will be prepared.

The novel compounds of formula (II), particularly those corresponding toformulae (IIb) and (IIa). ##STR35## in which ##STR36## represents thefollowing aromatic groups ##STR37## are obtained by condensation of thecompounds of formulae (IV) and (IVa): ##STR38## in which R" has the samemeanings as in (IIa) respectively, with homopiperazine and piperazine.This condensation is carried out preferably in solution in acetic acid.

The compounds of formula (IVa), particularly those in which ##STR39##are obtained by action of thionyl chloride, in a toluene solution oncorresponding cinnamoic acids of formula (V): ##STR40## in which R'₁₄represents the ethyl and isopropyl groups.

The compounds (V) are obtained by saponification of the ethyl esters ofthe corresponding cinnamoic acids of formula (VI): ##STR41## in whichR'₁₄ has the same meaning as in (V).

The compounds of formula (VI) were used in the crude state and areprepared by action of ethyl iodide or of isopropyl iodide on the ethylester of sinapic acid, in solution of acetonitrile and in the presenceof potassium carbonate.

The compounds of formula (III): ##STR42## are partially novel andparticularly those in which X' represents an oxygen atom and the Ar'radical represents:

(a) a mono or polysubstituted phenyl nucleus ##STR43## in which R'₂,R'₃, R'₄, R'₅ and R'₆ represent simultaneously the following values:

•R'₃ =R'₅ =R'₆ =H; R'₂ =F; R'₄ =COCH₃

•R'₃ =R'₅ =R'₆ =H; R'₂ =OCH₃ ; R'₄ =COCH₃, COEt

•R'₃ =R'₅ =R'₆ =H; R'₂ =Cl; R'₄ =COCH₃, NO₂

•R'₂ =R'₅ =R'₆ =H; R'₃ =CH₃ ; R'₄ =NO₂, NH-CONH-CH₃

•R'₅ =R'₆ =H; R'₂ =R'₃ =OCH₃ ; R'₄ =NHCONH-CH₃

•R'₃ =R'₅ =H; R'₂ =R'₆ =Cl; R'₄ =COCH₃, NYCONHCH₃

•R'₃ =R'₅ =H; R'₂ =R'₆ =OCH₃ ; R'₄ =COCH₃, COOEt, or NHCONHCH₃

•R'₅ =H; R'₃ =R'₄ =R'₆ =OCH₃ ; R'₂ =COCH₃

•R'₂ =R'₃ =R'₅ =R'₆ =H; R'₄ =CH₂ -CN

(b) a heterocycle of formula ##STR44## in which p, R'₇, R'₈ and R'₉assume the following values: •p=2; R'₇ =R'₈ =H; R'₉ represents themethoxy, acetoxy, methyl, cyano, acetyl, n-butyroyl, alkoxycarbonyl inwhich the alkyl is linear or branched and comprises 2 to 5 carbon atoms,cyclohexyloxy carbonyl, carboxamido, N-methyl carboxamido,N-cyclohexylcarboxamido, N-phenyl carboxamido, alkanoylamino whoselinear or branched alkyl has 1 to 4 carbon atoms,cyclohexylcarbonylamino, benzoylamino, N-alkylcarbamoylamino whoselinear or branched alkyl has from 1 to 5 carbon atoms,N-cyclohexylcarbamoylamino, N-phenylcarbamoylamino,N-(paramethoxyphenyl) carbamoylamino, N,N-dimethylcarbamoylamino,morpholino carbonylamino, N,N'-dimethyl carbamoylamino, orethoxycarbonylamino or the hydroxymethyl, cyanomethyl, ethylacetate,carboxamidomethyl or N-methylcarboxamidomethyl chains.

•p=2; R'₇ =R'₉ =H; R'₈ represents the acetyl group.

•p=2; R'₈ =R'₉ =H; R'₇ represents the acetamido group.

•p=1 or 3; R'₇ =R'₈ =H; R'₉ represents the acetyl, acetamido orN-methylcarbamoylamino groups.

(c) a naphthalene nucleus of the type ##STR45## in which R₁₀ representsthe acetyl, acetamido or N-methylcarbamoylamino groups.

(d) a heterocycle of the type ##STR46## in which q and R'₁₀ assumesimultaneously the following values: q=1 in which case R'₁₀ representsthe acetamido and N-methyl-carbamoylamino groups

q=2 in which case R'₁₀ represents the acetyl, acetamido orN-methylcarbamoylamino groups.

(e) the group ##STR47## and -X' represents a sulphur atom and the Ar'radical represents:

(f) an aromatic group ##STR48## in which R₁₁ represents the hydrogenatom or the methoxy group. (g) a heterocycle of the type ##STR49## inwhich R₁₃ represents the hydrogen atom or the acetyl group.

The compounds of formula (III) result from the condensation of thephenols of formula (VII):

    H--X'--Ar'                                                 (VII)

in which X' and Ar' have the same meaning as in formula (III), withepichlorohydrin or epibromohydrin. This condensation is carried outpreferably with reflux in acetone or acetonitrile in the presence ofpotassium carbonate.

The compounds of formula (VII) above are partially novel and are thenprepared following different methods according to the nature of X' andAr.

More exactly:

(1) The compounds of formula (VII) corresponding to formulae (VIIa),(VIIb), (VIIc): ##STR50## in which R"₂, R"₃, R"₅ and R"₆ assumesimultaneously the following values:

•R"₃ =R"₅ =R"₆ =H; R"₂ =CH₃

•R"₅ =R"₆ =H; R"₂ =R"₃ =OCH₃

•R"₃ =R"₅ =H; R"₂ =R"₆ =Cl

•R"₃ =R"₅ =H; R"₂ =R"₆ =OCH₃ ##STR51## in which q assumes the values 1or 2, are obtained by action of methyl isocyanate, in a chloroformsolution, respectively on the amino phenols of formulae: ##STR52## inwhich the values R"₂, R"₃, R"₅ and R"₆ have the same meanings as in(VIIa), ##STR53## in which q assumes the values 1 or 2.

(2) The compounds (VII) corresponding to the formula (VIId): ##STR54##in which q assumes the values 1 or 2, are obtained by condensation ofacetic anhydride on the (VIIIc) compounds in an aqueous solution.

(3) The compounds (VII) corresponding to formulae (VIIe) and (VIIf):##STR55## in which R₁₃ represents the hydrogen atom or the acetyl groupare obtained by treatment with a solution of NaOH in methanol ofcompounds of formulae (IX) and (IXa) ##STR56## in which R₁₃ representsthe hydrogen atom or the acetyl group.

The (IX) and (IXa) compounds are obtained by thermal transposition ofcompounds (X) and (Xa) ##STR57## in which R₁₃ has the same meanings asin (IXa).

The (X) and (Xa) compounds are themselves obtained by condensation ofN,N-dimethylthiocarbamoyl chloride with phenols of formulae: ##STR58##

(4) The compounds of formula (VII) corresponding to formula (VIIk)##STR59## in which p, R"₇, R"₈ and R"₉ assume simultaneously thefollowing values:

• p=2; R"₇ =R"₈ =H; R"₉ represents the acetoxy, cyano, alkoxy carbonylin which the alkyl is linear or branched and comprises 2 to 5 carbonatoms, cyclohexyloxy carbonyl, carboxamido, N-methyl carboxamido,N-cyclohexyl carboxamido, N-phenyl carboxamido, alkanoylamino whosealkyl is linear or branched and has 2 to 5 carbon atoms,cyclohexylcarbonylamino, benzoylamino, N-alkylcarbamoylamino whose alkylis linear or branched and has 1 to 5 carbon atoms,N-cyclohexylcarbamoylamino, N-phenylcarbamoylamino, N-paramethoxyphenylcarbamoylamino, N,N-dimethyl carbamoylamino, morpholinocarbonylamino,N,N'-dimethyl-carbamoylamino, or ethoxycarbonylamino group; or thehydroxymethyl, cyanomethyl, ethyl acetate, carboxamidomethyl andN-methylcarboxamido methyl chains,

• p=1 or 3; R"₇ =R"₈ =H; R"₉ then represents the acetyl, acetamino orN-methylcarbamoylamino groups,

are obtained by hydrogenolysis, in the presence of palladium oncharcoal, of compounds of formula (XI) ##STR60## in which p, R"₇, R"₈and R"₉ have the same meanings as in (VIIk).

(5) The (VII) compound corresponding to the formula VIIl) ##STR61## isobtained by the transposition of Fries of the compound of formula (XII)##STR62##

(6) The (VII) compound corresponding to formula (VIIm) ##STR63## isobtained by a Beckmann rearrangement, in an acetic acid medium, in thepresence of a hydrochloric acid, of the compounds of formula (XIII)##STR64##

Compound (XIII) is itself obtained by action of hydroxylamine on thecompound of formula (VIIi) ##STR65##

(7) The compound of formula (VII) corresponding to formula (VIIn)##STR66## is obtained by hydrogenolysis, in the presence of palladium on5% charcoal, of the compound of formula (XIp) used in the crude state##STR67##

The compounds of formula (XI) above, necessary in the preparation of thecompounds of formula (VIIk) are partly novel and are obtained bydifferent processes depending on the nature of p, R"₇, R"₈ and R"₉.

Similarly, the compound of formula (XIa) is novel: ##STR68## which canbe used for the synthesis of a compound of formula (VIIk'), which isknown: ##STR69## More exactly:

(1) The compound corresponding to formula (XIa) ##STR70## is obtained byaction of methyl sulfate on the compound of formula (XIV) ##STR71##

The compound (XIV) is obtained by action of potassium carbonate on thefollowing compound (XIb) ##STR72## which is itself obtained by BaeyerWilliger reaction on the compound of formula (XV) ##STR73##

The novel compound (XV) is obtained by action of benzyl chloride, insolution in acetonitrile or acetone, in the presence of potassiumcarbonate, on the compound (VIIi): ##STR74##

(2) The compounds (XI) corresponding to the formula (XIc): ##STR75## inwhich R₁₅ represents the ethyl, isopropyl, tert-butyl, n-pentyl, orcyclohexyl groups are obtained:

- when in (XIc) R₁₅ represents the isopropyl, t-butyl, n-pentyl, andcyclohexyl groups, by a synthesis in two stages which consists intreating the compound of formula (XVI) ##STR76## with thionyl chloride,then by reacting the crude product thus obtained with alcohols offormula (XVII):

    R.sub.15 --OH                                              (XVII)

in which R₁₅ has the same meaning as in formula (XIc), except for theethyl group, and

- when in (XIc) R₁₅ represents the ethyl group, by action of ethanol inthe presence of hydrochloric acid, on the compound of formula (XVI).

The compound of formula (XVI), also novel, is obtained by oxidation bythe iodine-pyridine complex, in the presence of soda, of the compound offormula (XV): ##STR77##

(3) The (XI) compounds corresponding to the formula (XId): ##STR78## inwhich R₁₆ represents either the hydrogen atom or the methyl, cyclohexylor phenyl groups are obtained:

- when R₁₆ assumes the above meanings, except for the methyl group, by atwo-stage synthesis which consists in treating the compound of formula(XVI) with thionyl chloride, then in reacting on the crude product thusobtained the amines of formula (XVIII)

    R.sub.16 --NH.sub.2                                        (XVIII)

in which R₁₆ represents the hydrogen atom or a cyclohexyl or phenylgroup, and

--when R₁₆ represents the methyl group, from the compound of formula(XVI) following the process of mixed anhydrides (with methylamine).

(4) The compounds (XI) corresponding to formula (XIe): ##STR79## inwhich R₁₇ represents either a linear or branched alkyl group having from2 to 5 carbon atoms, or the cyclohexyl group, or the phenyl group, areobtained by action of acid chlorides of formula (XIX):

    R.sub.17 COCL                                              (XIX)

in which R₁₇ has the same meanings as in (XIe), on the compounds offormula (XX): ##STR80## in a tetrahydrofuran medium.

(5) The compounds of formula (XI) corresponding to formula (XIf):##STR81## in which p and R₁₈ assume simultaneously the following values:• p=2; R₁₈ represents either a linear or branched alkyl group having 1to 5 carbon atoms or the cyclohexyl, phenyl or paramethoxyphenyl groups,

• p=1 or 3; R₁₈ represents the methyl group,

are obtained by action of isocyanates of formula (XXI):

    R.sub.18 NCO                                               (XXI)

on the compounds of formula (XX) above and (XXa) ##STR82## in which p'assumes the values 1 or 3.

(6) The compound (XI) corresponding to formula (XIg): ##STR83## isobtained by action of ethyl chloroformate on the compound of formula(XX) above.

The compounds of formulae (XX) and (XXa) used in the synthesis givenunder items (4), (5) and (6) above are novel and are obtained byhydrolysis, with potash (KOH) in ethanol, of the compounds of formula(XIh) ##STR84## in which p assumes the values 1, 2 or 3.

The compounds of formula (XIh) are, for their part, obtained:

--either by a Beckmann rearrangement, in an acid medium, of thecompounds of formula (XXII): ##STR85## in which p' assumes the values 1or 3.

--or by action of benzyl chloride on the compound of formula (VIIm):##STR86## in an acetone solution, in the presence of potassiumcarbonate.

The compounds of formula (XXII) above are obtained by action ofhydroxylamine on the compounds of formula (XIi): ##STR87## in which p'assumes the values 1 or 3.

The compounds of formula (XIi) are obtained by action of a di-iodated ordibrominated derivative of formula (XXIII):

    I--(CH.sub.2).sub.p' --I

or

    Br--(CH.sub.2).sub.p' --Br                                 (XXIII)

in which p' assumes the value 1 or 3, on the compound of formula (XXIV):##STR88## in solution in dimethyl sulfoxide or N,N-dimethylformamide inthe presence of potash (KOH).

Compound (XXIV) is obtained by action of benzyl chloride ongallacetophenone.

(7) The compound (XI) corresponding to formula (XIj): ##STR89## isobtained by action of methyl isocyanate on compound (XXV): ##STR90##Compound (XXV) is obtained by a synthesis in two steps which consists intreating the compound of formula (XX) with a mixture of formaldehyde anddimethyl-5,5-hydantoin in an ethanol solution, then in reacting on thecrude reaction product, sodium borohydride in solution indimethylsulfoxide, at a temperature of 100° C.

(8) Compound (XI) corresponding to formula (XIk): ##STR91## is obtainedby action of morpholine at reflux on the compound of formula (XIg):##STR92##

(9) Compound (XI) corresponding to formula (XIl): ##STR93## is obtainedby action of N,N-dimethylcarbamoyl chloride on the compound of formula(XX).

(10) Compound (XI) corresponding to formula (XIm): ##STR94## is obtainedby action of sodium cyanide on the compound of formula (XXVI): ##STR95##Compound (XXVI) is obtained by action of thionyl chloride on compound(XIp), hereafter described.

(11) Compound (XI) corresponding to formula (XIn): ##STR96## is obtainedby treating compound (XIm): ##STR97## by potash KOH in solution int-butanol.

(12) Compound (XI) corresponding to formula (XIo): ##STR98## is obtainedby action of methylamine following the mixed anhydride method on thecompound of formula (XXVII): ##STR99## Compound (XXVII) is obtained bysaponification with an aqueous solution of NaOH of compound (XIm).

(13) Compound (XI) corresponding to formula (XIp): ##STR100## isobtained by reduction with the double hydride of lithium and aluminum ofthe compound of formula (XIc), in which R₁₅ represents the ethyl group.

(14) Compound (XI) corresponding to formula (XIq): ##STR101## isobtained by action of phosphorous pentachloride on the compound (XId) inwhich R₁₆ represents the hydrogen atom.

(15) Compound (XI) corresponding to formula (XIr): ##STR102## isobtained by action of ethanol, in the presence of hydrochloric acid, onthe compound of formula (XXVII): ##STR103##

The process for the preparation of the compounds of formula (I) inwhich: ##STR104## or else

--the radical Ar represents ##STR105## consists in hydrolyzing theacetoxy group of compounds of formulae (Ia) and (Ib) with an alcoholsolution of sodium bicarbonate.

The compounds of formulae (Ia) and (Ib) are obtained by a processidentical to that used for the synthesis of compounds of formula (I)previously described.

The process for the preparation of the compounds of formula (I) in whichX represents the methylamino group: ##STR106## consists in condensing anepoxy of formula (IIIh): ##STR107## with N-methylaniline in an alcoholmedium.

The compound of formula (IIIh) is obtained by condensing epibromohydrinon 3,4,5-trimethoxy cinnamoylpiperazine of formula (IIc): ##STR108## insolution in acetonitrile, in the presence of potassium carbonate.

The process for the preparation of compounds of formula (I), in which R₁represents the hydrogen atom consists in condensing piperazine offormula (IIc) above with a chlorinated derivative of formula (XXVIII):##STR109## in which R₁₂ represents the acetyl, acetamido, N-methylcarboxamido or N-methylcarbamoyl amino groups in solution inacetonitrile, in the presence of potassium carbonate.

The novel compounds of formula (XXVIII) are obtained by condensation of1-bromo-3-chloro-propane with the phenols of formula (VII):

    H--X'--Ar'                                                 (VII)

in which X' represents the oxygen atom and Ar' is ##STR110## in whichR₁₂ has the same meanings as in formula (XXVIII).

The following preparations are given by way of example to illustrate theinvention.

EXAMPLE 1: 1-(4-cyano-2,3-ethylenedioxy-phenoxy)-2,3-epoxypropane (III)Code Number: 770584

A mixture of 31 g of 5-cyano-8-hydroxy-1,4-benzodioxane (VII) (Codenumber 770583), 38.35 g of epibromohydrin and 133 g of potassiumcarbonate in 300 ml of acetonitrile was brought to reflux for 12 hours.The mixture was filtered, the product then crystallized in the filtrate,it was filtered out and recrystallized in acetonitrile.

31.6 g of product were obtained.

Yield: 79%

Melting point: 167° C.

Empirical formula: C₁₂ H₁₁ NO₄

Molecular weight: 233.116

Elementary analysis:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated %                                                                              61.82      4.76       6.01                                        Obtained %  61.92      4.76       5.95                                        ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundsof formula (III), appearing in Table I below, were obtained.

                                      TABLE I                                     __________________________________________________________________________                                        Melting                                   Code                   Empirical                                                                            Molecular                                                                           Point                                                                              Yield                                                                             IR or NMR spectrum or            Number                                                                             X'  Ar'           Formula                                                                              Weight                                                                              °C.                                                                         %   elementary                       __________________________________________________________________________                                                 analysis                         780 008                                                                            oxygen                                                                             ##STR111##   C.sub.12 H.sub.14 O.sub.5                                                            238.232                                                                             110  83                                                                                 ##STR112##                      780 003                                                                            "                                                                                  ##STR113##   C.sub.13 H.sub.14 O.sub.6                                                            266.242                                                                             160  91  Elementary analysis: CH Cal.                                                  (%) 58.645.30 Obt. (%)                                                        58.605.43                        770 584                                                                            "                                                                                  ##STR114##   C.sub.12 H.sub.11 NO.sub.4                                                           233.116                                                                             167  79  Elementary analysis: CHN                                                      Cal. (%) 61.824.766.01 Obt.                                                   (%) 61.924.765.95                780 372                                                                            "                                                                                  ##STR115##   C.sub.15 H.sub.18 O.sub.6                                                            294.294    65                                                                                 ##STR116##                      780 368                                                                            "                                                                                  ##STR117##   C.sub.16 H.sub.11 O.sub.6                                                            305.296                                                                             57   87  Elementary analysis: CH Cal.                                                  (%) 62.326.54 Obt. (%)                                                        62.476.66                        780 300                                                                            "                                                                                  ##STR118##   C.sub.17 H.sub.21 O.sub.6                                                            321.338                                                                             83   77  Elementary analysis: CH Cal.                                                  (%) 63.246.88 Obt. (%)                                                        63.216.75                        780 332                                                                            "                                                                                  ##STR119##   C.sub.18 H.sub.21 O.sub.6                                                            333.348                                                                             79   64  Elementary analysis: CH Cal.                                                  (%) 64.666.63 Obt. (%)                                                        64.576.46                        770 204                                                                            "                                                                                  ##STR120##   C.sub.12 H.sub.13 NO.sub.5                                                           251.232                                                                             209  86.5                                                                               ##STR121##                      760 708                                                                            "                                                                                  ##STR122##   C.sub.13 H.sub.15 NO.sub.5                                                           265.258                                                                             132.5                                                                              89                                                                                 ##STR123##                      770 830                                                                            "                                                                                  ##STR124##   C.sub.18 H.sub.23 NO.sub.5                                                           333.372                                                                             102  75                                                                                 ##STR125##                      770 851                                                                            "                                                                                  ##STR126##   C.sub.18 H.sub.17 NO.sub. 4                                                          327.324                                                                             190  87                                                                                 ##STR127##                      770 544                                                                            "                                                                                  ##STR128##   C.sub.14 H.sub.17 NO.sub.5                                                           279.284                                                                             127  75                                                                                 ##STR129##                      770 600                                                                            "                                                                                  ##STR130##   C.sub.16 H.sub.21 NO.sub.5                                                           307.336                                                                             121  79                                                                                 ##STR131##                      770 691                                                                            "                                                                                  ##STR132##   C.sub.15 H.sub.19 NO.sub.5                                                           293.310                                                                             150  85                                                                                 ##STR133##                      770 613                                                                            "                                                                                  ##STR134##   C.sub.16 H.sub.21 NO.sub.5                                                           307.336                                                                             87   98                                                                                 ##STR135##                      770 532                                                                            "                                                                                  ##STR136##   C.sub.18 H.sub.25 NO.sub.5                                                           333.37                                                                              143  100                                                                                ##STR137##                      770 528                                                                            "                                                                                  ##STR138##   C.sub.18 H.sub.17 NO.sub.5                                                           372.324                                                                             153  90                                                                                 ##STR139##                      770 306                                                                            "                                                                                  ##STR140##   C.sub.14 H.sub.18 N.sub.2 O.sub.5                                                    294.300                                                                             196  90                                                                                 ##STR141##                      770 482                                                                            "                                                                                  ##STR142##   C.sub.15 H.sub.20 N.sub.2 O.sub.5                                                    308.326                                                                             176  68                                                                                 ##STR143##                      770 629                                                                            "                                                                                  ##STR144##   C.sub.15 H.sub.20 N.sub.2 O.sub.5                                                    308.326                                                                             155  85                                                                                 ##STR145##                      770 633                                                                            "                                                                                  ##STR146##   C.sub.16 H.sub.22 N.sub.2 O.sub.5                                                    322.362                                                                             186  69                                                                                 ##STR147##                      770 710                                                                            "                                                                                  ##STR148##   C.sub.16 H.sub.22 N.sub.2 O.sub.5                                                    322.352                                                                             146  28                                                                                 ##STR149##                      780 222                                                                            "                                                                                  ##STR150##   C.sub.19 H.sub.20 N.sub.2 O.sub.6                                                    372.366                                                                             220  85  Elementary analysis: CHN                                                      Cal. (%) 61.285.417.52 Obt.                                                   (%) 61.005.457.62                771 232                                                                            "                                                                                  ##STR151##   C.sub.14 H.sub.18 N.sub.2 O.sub.5                                                    294.300                                                                             160  80  Elementary analysis: CHN                                                      Cal. (%) 57.136.179.52 Obt.                                                   (%) 56.826.259.24                771 148                                                                            "                                                                                  ##STR152##   C.sub.16 H.sub.20 N.sub.2 O.sub.6                                                    336.336                                                                             164  55  Elementary analysis: CHN                                                      Cal. (%) 57.135.99 8.33 Obt.                                                  (%) 56.986.108.33                771 237                                                                            "                                                                                  ##STR153##   C.sub.14 H.sub.18 N.sub.2 O.sub.5                                                    294.300                                                                             oil  88                                                                                 ##STR154##                      770 524                                                                            "                                                                                  ##STR155##   C.sub.14 H.sub.17 NO.sub.6                                                           295.284                                                                             130  95                                                                                 ##STR156##                      770 311                                                                            "                                                                                  ##STR157##   C.sub.15 H.sub.18 O.sub.6                                                            294.294                                                                             72   85  Elementary analysis: CH Cal.                                                  (%) 61.216.17 Obt. (%)                                                        61.256.31                        770 385                                                                            "                                                                                  ##STR158##   C.sub.13 H.sub.15 NO.sub.5                                                           265.258                                                                             200  60                                                                                 ##STR159##                      770 381                                                                            "                                                                                  ##STR160##   C.sub.14 H.sub.17 NO.sub.5                                                           269.284                                                                             174.6                                                                              75                                                                                 ##STR161##                      780 307                                                                            "                                                                                  ##STR162##   C.sub.12 H.sub.12 O.sub.5                                                            236.216                                                                             80   85  Elementary analysis: CH                                                       Cal.(%) 61.015.12 Obt.(%)                                                     60.804.81                        780 345                                                                            "                                                                                  ##STR163##   C.sub.12 H.sub.13 NO.sub.5                                                           251.232                                                                             121  95                                                                                 ##STR164##                      780 408                                                                            "                                                                                  ##STR165##   C.sub.12 H.sub.14 N.sub.2 O.sub.5                                                    266.248                                                                             168  75                                                                                 ##STR166##                      780 240                                                                            "                                                                                  ##STR167##   C.sub.14 H.sub.15 O.sub.5                                                            263.260                                                                             72   96                                                                                 ##STR168##                      780 392                                                                            "                                                                                  ##STR169##   C.sub.14 H.sub.17 O.sub.5                                                            265.276                                                                             124  91                                                                                 ##STR170##                      780 467                                                                            "                                                                                  ##STR171##   C.sub.14 H.sub.18 N.sub.2 O.sub.5                                                    294.290                                                                             178  68                                                                                 ##STR172##                      760 845                                                                            "                                                                                  ##STR173##   C.sub.12 H.sub.14 O.sub.4                                                            222.232                                                                             66   92                                                                                 ##STR174##                      740 454                                                                            "                                                                                  ##STR175##   C.sub.13 H.sub.14 O.sub.5                                                            250.24                                                                              128      Elementary analysis: CH Cal.                                                  (%) 62.39 5.63 Obt. (%)                                                       62.15 5.79                       760 698                                                                            "                                                                                  ##STR176##   C.sub.14 H.sub.16 O.sub.6                                                            280.268                                                                             95   100                                                                                ##STR177##                      750 568                                                                            "                                                                                  ##STR178##   C.sub.13 H.sub.15 NO.sub.5                                                           265.26                                                                              180                                                                                     ##STR179##                      770 609                                                                            "                                                                                  ##STR180##   C.sub.15 H.sub.19 NO.sub.5                                                           293.310                                                                             133  76                                                                                 ##STR181##                      770 080                                                                            "                                                                                  ##STR182##   C.sub.18 H.sub.24 N.sub.2 O.sub.5                                                    348.388                                                                             220  70                                                                                 ##STR183##                      770 084                                                                            "                                                                                  ##STR184##   C.sub.18 H.sub.18 N.sub.2 O.sub.5                                                    342.34                                                                              208  75                                                                                 ##STR185##                      770 076                                                                            "                                                                                  ##STR186##   C.sub.13 H.sub.16 N.sub.2 O.sub.5                                                    280.274                                                                             235  40                                                                                 ##STR187##                      760 703                                                                            "                                                                                  ##STR188##   C.sub.12 H.sub.14 O.sub.5                                                            238.38                                                                              oil  93                                                                                 ##STR189##                      770 186                                                                            "                                                                                  ##STR190##   C.sub.13 H.sub.13 NO.sub.4                                                           247.242                                                                             138  86                                                                                 ##STR191##                      780 388                                                                            S                                                                                  ##STR192##   C.sub.11 H.sub.12 O.sub.3 S                                                          224.272                                                                             oil  85                                                                                 ##STR193##                      780 383                                                                            S                                                                                  ##STR194##   C.sub.13 H.sub.14 O.sub.4 S                                                          266.308                                                                             72   97                                                                                 ##STR195##                      __________________________________________________________________________

EXAMPLE 2: 2-methoxy-4-acetyl thiophenol (VIIe) Code Number: 780 472-1st step: 1-N,N-dimethylthiocarbamoyloxy-2-methoxy-4-acetylbenzene (X)Code Number: 780 470

A solution of 3.3 g of acetovanillone, of 2.9 g of dimethylthiocarbamoyl and of 8.2 g of potassium carbonate in 80 cm³ ofacetonitrile was brought to 70° C. for 30 minutes. After filtering, thesolvent was evaporated and the residue recrystallized in ethanol. 3.3 gof product were obtained.

Yield: 66%

Melting point: 130° C. ##STR196##

By the same process, but from the corresponding reagents, the followingcompounds of formula (Xa) were obtained:

5-N,N-dimethylthiocarbamoyloxy-1,4-benzodioxane

Code Number: 780 385

Yield: 98%

Melting point: 98° C.

Empirical form.: C₁₁ H₁₃ NO₃ S

Molecular weight: 239.39

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 55.21     5.48      5.85                                       Obtained (%)   55.10     5.40      5.62                                       ______________________________________                                    

5-N,N-dimethylthiocarbamoyloxy-8-acetyl-1,4-benzodioxane

Code Number: 780 380

Yield: 75%

Melting point: 149° C.

Empirical formula: C₁₃ H₁₅ NO₄ S

Molecular weight: 281.32

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 55.50     5.37      4.98                                       Obtained (%)   55.34     5.21      4.68                                       ______________________________________                                    

-2nd step: 1-N,N-dimethylcarbamoylthio-2-methoxy-4-acetylbenzene (IX)Code Number: 780 471

Under a flow of argon, 13 g of1-N,N-dimethylthiocarbamoyloxy-3-methoxy-4-acetylbenzene, obtained inthe preceding step were heated for 35 minutes at 250° C. Then, theresidue was chromatographed on a silica column. After elution withchloroform 6 g of product were obtained:

Yield: 46%

Melting point: 116° C.

    ______________________________________                                        NMR spectrum δ ppm = 7.57, s, aromatic protons                          = 3.91, s, : OMe                                                               ##STR197##                                                                   = 2.52, s, : COCH.sub.3                                                       ______________________________________                                    

By the same process, but from the corresponding reagents, the followingcompounds of formula (IXa) were obtained:

5-N,N-dimethylcarbamoylthio-1,4-benzodioxane

Code Number: 780 386

Yield: 59%

Melting point: 78° C.

    ______________________________________                                        NMR spectrum: δ ppm = 6.98, m; and 4.22, s: benzo-                      dioxan protons                                                                 ##STR198##                                                                   ______________________________________                                    

IR spectrum: band at 1640 cm⁻¹ ##STR199##

5-N,N-dimethylcarbamoylthio-8-acetyl-1,4-benzodioxane

Code Number: 780 381

Yield: 39%

Melting point: 155° C.

Empirical formula: C₁₃ H₁₅ NO₄ S

Molecular weight: 281.32

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 55.50     5.37      4.98                                       Obtained (%)   55.73     5.54      5.05                                       ______________________________________                                    

-3rd step: 2-methoxy-4-acetylthiophenol (VIIe) Code Number: 780 472

A solution of 5.6 g of 4-N,N-dimethylthiocarbamoyloxy-3-methoxyacetophenone obtained in the previous step, 2.6 g of soda (NaOH) in 210ml of methanol and 60 ml of water was brought to reflux for two hours.Then, the solvents were evaporated, the residue was taken up in water,washed with ethyl acetate, the aqueous phase was acidified withconcentrated hydrochloric acid, extracted with chloroform which wasdried and the solvent was evaporated. 3.5 g of product were obtained.

Yield: 87%

Melting point: 50° C.

    ______________________________________                                        NMR spectrum: δ ppm                                                                     = 7.20, m: aromatic protons                                                   = 4.16, s: -SH                                                                = 3.96, s, : -OMe                                                             = 2.57, s, : -COCH.sub.3                                      ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundsof formula (VIIf), code numbers 780 387 and 780 382, shown in Table IIbelow, were obtained.

EXAMPLE 3: 5-hydroxy-8-N-cyclohexyl carboxamido-1,4-benzodioxane (VIIk)Code Number: 770 829

A solution of 34.5 g of5-benzyloxy-8-N-cyclohexylcarboxamido-1,4-benzodioxane (XIId), codenumber 770 828, in presence of 6.8 g of palladium on 5% charcoal washydrogenolysed in an autoclave at room pressure and temperature. Oncethe absorption of hydrogen was completed, and after filtration, thefiltrate was evaporated.

Yield: 92%

Melting point: 182° C.

    ______________________________________                                        NMR spectrum: δ ppm = 7.24, d; 6.48, d, (J = 10Hz) and                          4.18 s, : benzodioxane protons                                               = 7.62, d, (J = 7Hz): CONH                                                    = 10.1, m, : OH                                                                ##STR200##                                                            ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundsof formula (VII), corresponding to formula (VIIk) shown in Table IIbelow, were obtained.

EXAMPLE 4: 5-hydroxy-8-n-propylcarbonyl-1,4-benzodioxane (VIII) CodeNumber: 750 769

A solution of 44.4 g (0.2 mole) of 8-n-propylcarbonyloxy-1,4-benzodioxane in 240 ml of nitrobenzene was cooled to atemperature of less than 10° C. and 40 g (0.3 mole) of aluminum chloridewere slowly added. It was left for 48 hours at room temperature, dilutedwith water, the organic phase was decanted, the solvent was evaporated,and the residue was chromatographed on a silica column. Withtoluene-chloroform mixtures, 27 g (61%) of5-hydroxy-6-n-propylcarbonyl-1,4-benzodioxane were eluted. Then, with a90% chloroform-10% methanol mixture, 5 g of5-hydroxy-8-n-propylcarbonyl-1,4-benzodioxane-1,4 were eluted.

Yield: 11%

Melting point: 84° C.

Empirical formula: C₁₂ H₁₄ O₄

Molecular weight: 222.23

Elementary analysis:

    ______________________________________                                                         C    H                                                       ______________________________________                                        Calculated (%)     64.87  6.35                                                Obtained (%)       64.84  6.24                                                ______________________________________                                    

EXAMPLE 5: 5-hydroxy-8-acetamido-1,4-benzodioxane (VIIm) Code number:750 548 -1st step: 5-hydroxy 8-acetyl-1,4-benzodioxane oxime (XIII) Codenumber: 750 527

A solution of 19.4 g (0.1 mole) of 5-hydroxyl 8-acetyl-1,4-benzodioxane(VIIi) and 10.4 g (0.15 mole) of hydroxylamine hydrochloride in 50 ml ofpyridine and 50 ml of ethanol was brought to reflux for 7 hours. Then,the solvents were evaporated and the residue crystallized in water. 12 gof product were obtained.

Yield: 55%

Melting point: 145° C.

Empirical form.: C₁₀ H₁₁ NO₄ 1/2H₂ O

Molecular weight: 218.20

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 55.04     5.54      6.42                                       Obtained (%)   55.24     5.68      6.31                                       ______________________________________                                    

-2nd step: 5-hydroxy-8-acetamido-1,4-benzodioxane

250 ml of acetic acid were saturated with gaseous hydrochloric acid,then 20.9 g (0.1 mole) of 5-hydroxy-8-acetyl-1,4-benzodioxane oxime,obtained in the previous step, were added. It was brought to reflux for5 hours, then the solvents were evaporated, the residue was crystallizedin water and recrystallized in ethanol. 7 g of product were obtained.

Yield: 33%

Melting point: 170° C.

Empirical formula: C₁₀ H₁₁ NO₄

Molecular weight: 209.20

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 57.41     5.30      6.70                                       Obtained (%)   57.17     5.31      6.54                                       ______________________________________                                    

EXAMPLE 6: 5-hydroxy-8-methyl-1,4-benzodioxane (VIIn) Code number: 760844

A solution of 14.7 g (0.05 mole) of5-benzyloxy-8-hydroxymethyl-1,4-benzodioxane (XIp) code number 760 701,crude, non-crystallized, in 300 ml of absolute alcohol washydrogenolysed at room pressure and temperature, in the presence of 3 gof palladium on 5% charcoal. Once the absorption of hydrogen wascompleted, the catalyst was filtered and the solvent was evaporated. Aliquid was obtained.

NMR spectrum:

    ______________________________________                                        δ ppm                                                                              = 8.90, s, 1 phenolic proton                                                  = 6.42 and 6.21, d, (J=10Hz)                                                  = 4.17, s,: benzodioxane protons                                              = 1.98, s,: --CH.sub.3                                             ______________________________________                                    

EXAMPLE 7: 5-benzyloxy-8-methoxy-1,4-benzodioxane (XIa) Code number: 780006 -1st step: 5 benzyloxy-8-acetyl-1,4-benzodioxane (XV) Code Number:760 694

A suspension of 97 g (0.5 mole) of 5 hydroxy-8-acetyl-1,4-benzodioxane(VIIi), of 127 g (1 mole) of benzyl chloride and 155 g (1.12 mole) ofpotassium carbonate in 150 ml of absolute alcohol was brought to refluxfor 24 hours. After filtration the solvent was evaporated, the residuewas taken up in chloroform, washed with a solution of soda (NaOH) 1 N,the solvent was evaporated and the product was crystallized in alcohol,135 g of product expected were obtained.

Yield: 95%

Melting point: 133° C.

Empirical formula: C₁₇ H₁₆ O₄

Molecular weight: 284.29

Elementary analysis:

    ______________________________________                                                         C    H                                                       ______________________________________                                        Calculated (%)     71.82  5.67                                                Obtained (%)       71.76  5.76                                                ______________________________________                                    

-2nd step: 5-benzyloxy-8-acetoxy-1,4-benzodioxane (XIb) Code Number: 780001

To a solution of 58 g of 5-benzyloxy-8-acetyl-1,4-benzodioxane (XV)obtained in the previous step, in 300 ml of formic acid, were added, at-5° C., 25 g of a 36% solution of hydrogen peroxide in 100 ml of formicacid. The mixture was left at 0° C. for 72 hours then poured on amixture of water and ice, the precipitate formed was filtered, washed inwater and recrystallized in a mixture of ethyl acetate and isopropylether.

Yield: 89%

Melting point: 104° C.

Empirical formula: C₁₇ H₁₆ O₅

Molecular weight: 300.39

Elementary analysis:

    ______________________________________                                                         C    H                                                       ______________________________________                                        Calculated (%)     67.97  5.37                                                Obtained (%)       68.15  5.55                                                ______________________________________                                    

-3rd step: 5-benzyloxy-8-hydroxy-1,4-benzodioxane (XIV) Code Number: 780005

To a solution of 58.3 g of 5-benzyloxy-8-acetoxy-1,4-benzodioxaneobtained in the previous step, in 400 ml of methanol, are added 75 g ofpotassium carbonate, at room temperature. Then, after 30 minutes, thesolution was filtered, the solvent evaporated, and the residue was takenup in water and acidified in concentrated hydrochloric acid. Theprecipitate obtained was filtered and recrystallized in alcohol: 47.3 gof the product were obtained.

Yield: 94%

Melting point: 131° C.

Empirical formula: C₁₅ H₁₄ O₄

Molecular weight: 258.25

Elementary analysis:

    ______________________________________                                                         C    H                                                       ______________________________________                                        Calculated (%)     69.75  5.46                                                Obtained (%)       69.83  5.39                                                ______________________________________                                    

-4th step: 5-benzyloxy-8-methoxy-1,4-benzodioxane (XIa) Code Number: 780006

To a solution of 45 g of 5-benzyloxy-8-hydroxy-1,4-benzodioxane obtainedin the preceding step and 52 g of potassium carbonate in 500 ml ofacetone, there was slowly added 33.5 g of dimethylsulfate then 20 ml ofa 10% solution of methanolic caustic potash. The solution was thenbrought to reflux for 2 hours and 30 minutes, filtered, the solventswere evaporated, the residue was taken up in ethyl ether, washed withwater, dried and the solvent was evaporated. 47 g of product wereobtained.

Yield: 98%

Melting point: 70° C.

NMR Spectrum:

    ______________________________________                                        δ ppm                                                                              = 7.36, d, and 6.47, d, (J=2Hz) and                                            4.23, s, benzodioxane protons                                                = 7.35, m and 5.03, s: -CH.sub.2 -φ                                       = 3.78, s, : -OCH.sub.3                                            ______________________________________                                    

EXAMPLE 8: 5-benzyloxy-8-isopropoxycarbonyl-1,4-benzodioxane (XIc) CodeNumber: 780 370 -1st step: (5-benzyloxy-1,4-benzodioxane)yl-8-carboxylicacid (XVI) Code Number: 760 695

To a solution of 29 g (0.1 mole) of5-benzyloxy-8-acetyl-1,4-benzodioxane (XV) obtained in the first step ofExample 7, in 150 ml of pyridine were added 25.8 g (0.1 mole) of iodine.Then, the mixture was brought to 100° C. for 1 hour, the excess ofpyridine was driven off, the residue was taken up in water, filtered andthe precipitate obtained was put in solution in 450 ml of a 50/50alcohol-water mixture. A solution of 70 g of soda (NaOH) in 200 ml ofwater was slowly added, then, washing with chloroform was carried outand the precipitate formed was filtered and dissolved in an aqueoussolution of soda (NaOH). Acidification was carried out up to pH≃1 bymeans of hydrochloric acid, then it was concentrated and filtered. 25 gof product were obtained.

Yield: 35%

Melting point: ≃200° C.

Empirical formula: C₁₆ H₁₄ O₅

Molecular weight: 286.27

Elementary analysis:

    ______________________________________                                                         C    H                                                       ______________________________________                                        Calculated (%)     67.12  4.93                                                Obtained (%)       66.91  5.00                                                ______________________________________                                    

-2nd step: 5-benzyloxy-8-isopropoxycarbonyl-1,4-benzodioxane

To a toluene solution of 31 g of (5-benzyloxy-1,4-benzodioxane)ylcarboxylic acid obtained in the previous step, 50 ml of thionyl chloridewere added and the mixture was brought to 70°-80° C. for 2 hours. Then,the solvents were evaporated, the residue was dissolved in 200 ml oftetrahydrofuran, and 15 cm³ of isopropyl alcohol and 70 cm³ oftriethylamine were added. The mixture was brought to 60° C. for 3 hours,then the precipitate formed was filtered, the filtrate evaporated andthe residue chromatographed on a silica column and eluted withchloroform. 20 g of product were obtained which was recrystallized inisopropyl ether.

Yield: 71%

Melting point: 96° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                             7.38 (d), and 6.57, d, (J = 10Hz) and                                         4.23, s, benzodioxane protons                                     =           7.28, s, and 5.08 s: CH.sub.2 -φ                              =           5.09, quintet, and 1.14, d (J = 6 Hz)                                          ##STR201##                                                       ______________________________________                                    

IR spectrum: 1710 and 1200 cm⁻¹ band: ##STR202##

With the same method, but from the corresponding reagents, the compoundsof formula XIc was prepared, given in Table III and bearing code numbers780 366, 780 298 and 780 330.

EXAMPLE 9: (5-benzyloxy-1,4-benzodioxane)yl-8 ethyl carboxylate (XIc)Code Number: 760 696

A solution of 25 g (0.095 mole) of(5-benzyloxy-1,4-benzodioxane)yl-8-carboxylic acid obtained in the firststep of Example 8, in 500 ml of alcohol and 50 ml of a solution ofhydrochloric acid in 4.4 N ethanol was brought to reflux for 4 hours.Then, the solvent was evaporated, the residue was taken up inchloroform, washed with a solution of sodium bicarbonate, with water,then it was dried, and the solvent was evaporated. 26 g of ester wereobtained.

Yield: 90%

IR spectrum: band at 1708 and 1200 cm⁻¹ (COOEt)

NMR spectrum:

    ______________________________________                                        δppm =                                                                            7.22, d; 6.51, d; (J = 10Hz) and                                              4.38, s, : benzodioxane protons                                     =         7.18, s: benzylic aromatic protons                                  =         5.20, s: O--CH.sub.2 --φ                                        =         4.35, q, and 1.35, t, (J = 8 Hz): COOEt.                            ______________________________________                                    

EXAMPLE 10: 5-benzyloxy-8-N-cyclohexyl carboxamido-1,4-benzodioxane(XId) Code Number: 770 828

To a toluene solution of 30 g of(5-benzyloxy-1,4-benzodioxane)yl-8-carboxylic acid obtained in the firststep of Example 8, were added 30 cm³ of thionyl chloride and it wasbrought to 70°-80° C. for 2 hours. Then, the solvents were evaporated,the residue was dissolved in 200 ml of tetrahydrofuran and 24 ml oftriethylamine and 19 ml of cyclohexylamine were added. The mixture wasbrought to 60° C. for 3 hours and after filtration the filtrate wasevaporated and the residue recrystallized in a mixture of ethyl acetateand hexane.

Yield: 82.5%

Melting point: 117° C.

Empirical formula: C₂₂ H₂₅ NO₄

Molecular weight: 367.49

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 71.91     6.86      3.81                                       Obtained (%)   71.99     6.78      3.69                                       ______________________________________                                    

With the same method, but from the corresponding reagents, the compoundsof formula XId were obtained, given in Table III and bearing thefollowing code numbers 770 202 and 770 849.

EXAMPLE 11: 5-benzyloxy-8-N-methylcarboxamido-1,4-benzodioxane (XId)Code Number: 760 706

To a solution cooled below 0° C. of 20 g (0.07 mole) of(5-benzyloxy-1,4-benzodioxane)yl-8-carboxylic acid obtained in the 1ststep of Example 8, in 200 ml of anhydrous tetrahydrofuran, 11 ml oftriethylamine were added, then 6.9 ml of ethyl chloroformate. It wasstirred at 0° C. for 2 hours, then a gaseous flow of methylamine waspassed for 90 minutes. Then, the solution was left for one hour at roomtemperature, the tetrahydrofuran was evaporated, the residue was takenup in chloroform, then it was washed with water, the solvent wasevaporated and recrystallized in alcohol. 18 g of product were obtained.

Yield: 80%

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            7.70, d; 6.60, d, (J = 10Hz) and 4.32,                                        s, : benzodioxane protons                                          =          5.18, s, : OCH.sub.2 -φ                                        =          7.36, m, NHCO                                                       =                                                                                        ##STR203##                                                        ______________________________________                                    

EXAMPLE 12: 5-benzyloxy-8-propionamido-1,4-benzodioxane (XIe) CodeNumber: 770 542

To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX); codenumber 760 727, in 250 ml of chloroform and 21.3 ml of triethylamine,cooled to 0° C., 12.1 cm³ of propionyl chloride were slowly added. Then,it was stirred for 17 hours, washed with a solution of dilutedhydrochloric acid, with water, with an aqueous solution of sodiumbicarbonate, then with water, the organic phase was evaporated and theresidue recrystallized in ethyl acetate.

Yield: 73%

Melting point: 139° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            7.42, d; 6.51, d, (J = 10Hz) and 4.20,                                        s: benzodioxane protons                                            =          7.78, d, (J = 9Hz): --NH--CO--                                     =          7.35, s and 5.03, s: CH.sub.2 --φ                              =          2.17, q, and 1.11, t (J = 7Hz):                                               CO--CH.sub.2 --CH.sub.3                                            ______________________________________                                    

IR spectrum: bands at 3400, 1670 and 1510 cm⁻¹ : --NH--CO--

With the same method, but from the corresponding reagents, the compoundsof formula XIe were obtained, appearing in Table III and bearing codenumbers 770 689; 770 611; 770 530; 770 526 and 770 607.

EXAMPLE 13: 4-benzyloxy-2,3-methylene dioxy aniline (XXa) Code Number:780 405

A solution of 34 g of 4-benzyloxy-2,3-methylene dioxy acetanilide (XIh),code number 780 343, in 120 ml of methanol was treated with 34 g ofpotassium hydroxide, for 11/2 hour at reflux. Then, the precipitateformed was filtered and recrystallized in isopropyl alcohol, 13.4 g ofproduct were obtained.

Yield: 50%

Melting point: 59° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                           6.22, q, (J = 9Hz) aromatic protons of                                        the benzodioxole group                                               =                                                                                       ##STR204##                                                         =         7.36, s and 5.03, s, : CH.sub.2 -φ                              =         3.17, s, NH.sub.2                                                   ______________________________________                                    

With the same method, but from the corresponding reagents, were obtainedthe compounds of formula (XXa), code number 780 464:6-benzyloxy-9-amino-1,5-benzodioxepine.

Yield: 82%

Melting point: 92° C.

Empirical formula: C₁₆ H₁₇ NO₃

Molecular weight: 217.29

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 70.89     6.32      5.16                                       Obtained (%)   70.72     6.39      5.13                                       ______________________________________                                    

as well as the compound of formula (XX), code number 760 727:5-benzyloxy-8-amino-1,4-benzodioxane:

Yield: 78%

Melting point: 130° C.

Empirical formula: C₁₅ H₁₅ NO₃

Molecular weight: 257.28

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 70.02     5.88      5.44                                       Obtained (%)   69.73     5.94      5.24                                       ______________________________________                                    

EXAMPLE 14: 4-benzyloxy-2,3-methylene dioxy-2,3-acetanilide (XIh) CodeNumber: 780 343

To a suspension of 100 g of 4-benzyloxy-2,3-methylene dioxy-2,3acetophenone oxime (XXII), code number 780 342, in 500 ml of aceticacid, 500 ml of acetic anhydride were slowly added, then a gaseous flowof hydrochloric acid was passed at 10° C., for 1 hour. Then, thesolution was brought to 40°-50° C. for 5 hours, the solvents wereevaporated, the residue was taken up with chloroform, then it was washedwith water, the solvent was evaporated and the residue recrystallized inethyl acetate.

Yield: 84%

Melting point: 148° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                           7.18, m and 5.18 s : CH.sub.2 φ                                 =         7.18, m (aromatic protons of the benzo-                                       dioxole nucleus and of CH.sub.2 φ)                               =                                                                                       ##STR205##                                                         =         2.09, s, CH.sub.3 CON                                               =         6.51 d, (J = 9Hz) : NHCO                                            ______________________________________                                    

IR spectrum: 3260, 1650 cm⁻¹ : band --NH--CO--

With the same method but from the corresponding reagents, the compoundof formula (XIh) was obtained, code number 780 463, appearing in TableIII.

EXAMPLE 15: 4-benzyloxy-2,3-methylene dioxy acetophenone oxime (XXII)Code Number: 780 342

A solution of 192 g of 4-benzyloxy-2,3-methylene dioxy acetophenone(XIi); code number 780 305 and of 64 g of hydroxylamine hydrochloride in500 ml of pyridine and 500 ml of ethanol were brought to reflux for 2hours. Then, the solvents were evaporated, the residue was taken up inwater and the precipitate formed was filtered.

Yield: 98%

Melting point: 168° C.

Empirical formula: C₁₆ H₁₅ NO₄

Molecular weight: 285.29

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 67.36     5.30      4.91                                       Obtained (%)   67.31     5.30      4.91                                       ______________________________________                                    

With the same method, but from the corresponding reagents,6-benzyloxy-9-acetyl-1,5-benzodioxepine oxime (XXII) was obtained, codenumber 780 390.

Yield: 90%

Melting point: 134° C.

NMR Spectrum:

    ______________________________________                                        δ ppm =                                                                            13.00, m, = N--OH                                                  =          6.51, d; 6.88, d, (J = 10Hz); 4.10, m;                                        and 2.08, m: benzodioxepine protons                                =          5.17 s and 7.19, s: CH.sub.2 --φ                               =          2.20, s: --CH.sub.3                                                ______________________________________                                    

EXAMPLE 16: 5-benzyloxy-8-acetamido-1,4-benzodioxane (XIh) Code Number:760 606

Following the working method described in the first step of Example 7,but from 5-hydroxy-8-acetamido-1,4-benzodioxane (VIIm), code number 750548, 91% of product was obtained.

Melting point: 148° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            7.35, d; 6.56, d, (J = 10Hz) and 4.24, s,                                     benzodioxane protons                                               =          7.36, s, and 5.07, s, : CH.sub.2 --φ                           =          7.76, d, (J = 9Hz): NH--CO--                                       =          2.17, s, : CH.sub.5                                                ______________________________________                                    

IR spectrum: bands at 3270, and 1660 cm⁻¹ : --NH--CO--CH₃

EXAMPLE 17: 5-benzyloxy-8-N-ethyl carbamoyl amino-1,4-benzodioxane (XIf)Code Number: 770 304

For 20 hours a mixture of 25 g of 5-benzyloxy-8-amino-1,4-benzodioxane,code number 760 727, and 8 ml of ethyl isocyanate in 300 ml ofchloroform was maintained at reflux. Then, the solvents were evaporatedin a vacuum and the residue recrystallized in ethanol.

Yield: 80%

Melting point: 188° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            7.41, d; 6.56, d, (J = 10Hz) and 4.19, s,                                     benzodioxane protons                                               =          7.38, s, and 4.97, s, : --CH.sub.2 --φ                         =          6.60, m and 7.40, m: NH--CO--NH                                    =          3.02, q and 1.00, t, (J = 7Hz):                                               --CH.sub.2 --CH.sub.3 --                                           ______________________________________                                    

With the same method, but from the corresponding reagents, the compoundsof formula (XIf) were obtained, appearing in Table III and bearing thecode numbers 770 074, 770 480, 770 627, 770 631, 770 708, 770 078, 770082, 770 220, 780 406 and 780 465.

EXAMPLE 18: 5-benzyloxy-8-ethoxy carbonylamino-1,4-benzodioxane (XIg)Code Number: 770 522

To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX), codenumber 760 727, in 250 ml of chloroform, 21.3 ml of triethylamine, thenslowly, at 0° C., 15.2 g of ethyl chloroformate were added. The solutionwas stirred for 7 hours, filtered and the filtrate was washed with adiluted hydrochloric acid solution, with water, with a solution ofsodium bicarbonate and with water. The solvent was evaporated and theresidue recrystallized in ethylacetate.

Yield: 74%

Melting point: 108° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            6.52, d; 7.41, d, (J = 10Hz) and 4.22,                                        s, : benzodioxane protons                                          =          7.38, s and 5.08, s : CH.sub.2 --φ                             =          4.10, q, and 1.14, t, (J = 7Hz):                                              CH.sub.2 --CH.sub.3                                                =          6.80, s, --NH--                                                    ______________________________________                                    

IR spectrum: 3315 and 1692 cm⁻¹ =NHCOOEt

EXAMPLE 19: 4-benzyloxy-2,3-methylene dioxy acetophenone (XIi) CodeNumber: 780 305

A mixture of 140 g of 4-benzyloxy-2,3-dihydroxy acetophenone (XXIV),code number 780 304, 295 g of diiodomethane and 300 g of potassiumcarbonate in 1200 ml of dimethyl formamide was brought to reflux for 5hours. After filtering, the filtrate was evaporated, the residue wastaken up in a 50/50 mixture of ethyl acetate and ether, then it waswashed with water, the organic phase was evaporated and the residue wascrystallized in ethanol.

Yield: 93%

Melting point: 101° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            6.55, d; 7.35, d, (J = 10Hz) : aromatic                                       protons of the benzodioxole nucleus                                 =                                                                                        ##STR206##                                                        =          7.38, s and 5.18, s, : CH.sub.2 -φ                             =          2.44 s, : CH.sub.3                                                 ______________________________________                                    

IR spectrum: 1670 cm⁻¹ : --CO--CH₃

With the same method, but from the corresponding reagents, the compound(XIi), code number 780 238, given in Table III, was obtained.

EXAMPLE 20: 4-benzyloxy-2,3-dihydroxy acetophenone (XXIV) Code Number:780 304

A mixture of 349 g of gallacetophenone, 1750 g of sodium bicarbonate and260 g of benzyl chloride in 4000 ml of acetone were stirred for 2 hoursat room temperature. Then the mixture was brought to reflux for 36hours, filtered, the solvent was evaporated and the residue was taken upin ethyl acetate and diluted in isopropyl ether. 58% of crystallizedproduct were obtained.

Melting point: 128° C.

Empirical formula: C₁₅ H₁₄ O₄

Molecular weight: 258.26

Elementary analysis:

    ______________________________________                                                         C        H                                                   ______________________________________                                        Calculated (%)     69.75      5.46                                            Obtained (%)       69.48      5.60                                            ______________________________________                                    

EXAMPLE 21 : 5-benzyloxy-8-N,N'-dimethyl carbamoylamino-1,4-benzodioxane (XIj) Code Number: 771 235 -First step:5-benzyloxy-8-N-methylamino-1,4-benzodioxane (XXV) Code Number: 771 234

A mixture of 40 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX), codenumber 760 727, 120 ml of formaldehyde (at 38% in an aqueous solution)and 29 g of 5,5-dimethylhydantoin in 300 ml of ethanol was brought toreflux for 12 hours. Then the solvent was evaporated, the residue wastaken up in chloroform and washed by means of a diluted hydrochloricacid solution. The organic phase was evaporated and the residuedissolved in 500 ml of dimethylsulfoxide. 23 g of sodiumborohydride wereslowly added, and brought to 100° C. for 30 minutes. Then it was dilutedin 1500 ml of water, extracted with chloroform, washed with water andthe solvent evaporated. The residue was chromatographed on a silicacolumn. Eluted with chloroform, 34% of product was obtained.

Melting point: 62° C.

Empirical formula: C₁₆ H₁₇ NO₃

Molecular weight: 271.30

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 70.83     6.32      5.16                                       Obtained (%)   70.70     6.29      4.90                                       ______________________________________                                    

-Second step: 5-benzyloxy-8-N,N'-dimethyl carbamoylamino-1,4-benzodioxane

A mixture of 22.4 g of 5-benzyloxy-8-N-methyl amino-1,4-benzodioxane,obtained from the preceding step, and 10 ml of methyl isocyanate in 100ml of chloroform were brought to reflux for 2 hours, then the solventwas evaporated and the residue recrystallized in alcohol:

Yield: 74%

Melting point: 140° C.

Empirical formula: C₁₈ H₂₀ N₂ O₄

Molecular weight: 328.36

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 65.84     6.14      8.53                                       Obtained (%)   65.71     6.07      8.62                                       ______________________________________                                    

EXAMPLE 22: 5-benzyloxy-8-morpholinocarbonylamino-1,4-benzodioxane (XIk)Code Number: 771 146

A mixture of 38 g of 5-benzyloxy-8-ethoxycarbonylamino-1,4-benzodioxane(XIg), code number 770 522, and 300 ml of morpholine was brought toreflux for 16 hours, in the presence of a pinch of ammonium chloride.Then the morpholine in excess was evaporated and the residue wasrecrystallized in 96° ethanol.

Yield: 72%

Melting point: 184° C.

Empirical formula: C₂₀ H₂₂ N₂ O₅

Molecular weight: 370.39

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 64.85     5.67      7.56                                       Obtained (%)   64.85     5.95      7.74                                       ______________________________________                                    

EXAMPLE 23: 5-benzyloxy-8-N,N-dimethylcarbamoyl amino-1,4-benzodioxane(XIl) Code Number: 771 230

To a solution of 100 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX),code number 760 727, and 100 ml of triethylamine, in 1000 ml ofchloroform were slowly added 47 ml of dimethylcarbamoyl chloride, atroom temperature, then it was brought to reflux for 48 hours. Afterfiltering, the filtrate was evaporated and the residue wasrecrystallized in ethanol. 60 g of product were obtained.

Yield: 47%

Melting point: 142° C.

Empirical formula: C₁₈ H₂₀ N₂ O₄

Molecular weight: 328.36

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 65.84     6.14      8.53                                       Obtained (%)   65.67     6.35      8.25                                       ______________________________________                                    

EXAMPLE 24: 5-benzyloxy-8-cyanomethyl-1,4-benzodioxane (XIm) CodeNumber: 770 119 -First step: 5-benzyloxy-8-chloromethyl-1,4-benzodioxane(XXVI) Code Number: 770 188

To a solution, cooled to -10° C., of 10 g (0.037 mole) of5-benzyloxy-8-hydroxymethyl-1,4-benzodioxane (XIp), code number 760 701,in 100 ml of chloroform were slowly added 4.6 g (0.039 mole) of thionylchloride. They were left in contact for 15 minutes, then the solventswere evaporated, the residue was taken up in chloroform, washed with asolution of sodium bicarbonate, dried and the solvent was evaporated.10.4 g of unstable product were obtained which, after checking bychromatography on a thin silica layer, was used in the synthesis of thecompound of formula (XIm), code number 770 119.

-Second step: 5-benzyloxy-8-cyanomethyl-1,4-benzodioxane

A solution of 99 g (0.34 mole) of5-benzyloxy-8-chloromethyl-1,4-benzodioxane, obtained in the previousstep, 19 g (0.4 mole) of sodium cyanide and 0.5 g of sodium iodide in1000 ml of anhydrous dimethylformamide was brought to 60° C. for 45minutes. Then the solvent was driven off in a vacuum, the residue wastaken up in 600 ml of a saturated solution of sodium bicarbonate and 300ml of chloroform, the organic phase was decanted, dried and the solventevaporated. 85 g of product were obtained.

Yield: 89%

Melting point: 95° C.

Empirical formula: C₁₇ H₁₅ NO₃

Molecular weight: 281.29

Elementary analysis:

    ______________________________________                                                     C       H         N                                              ______________________________________                                        Calculated (%) 72.58     5.18      4.98                                       Obtained (%)   72.15     5.47      4.84                                       ______________________________________                                    

EXAMPLE 25: 5-benzyloxy-8-carboxamidomethyl-1,4-benzodioxane (XIn) CodeNumber: 770 383

To a solution of 50 g of 5-benzyloxy-8-cyanomethyl-1,4-benzodioxane,obtained in the process of Example 24, in 250 ml of t-butanol wereslowly added 39 g of pulverized potassium hydroxide, then it was broughtto reflux for 20 minutes. Then the mixture was poured into 500 ml of anaqueous solution of sodium chloride, extracted with chloroform, washedwith water, the solvent was evaporated and the residue recrystallized inethanol.

Yield: 90%

Melting point: 166° C.

NRM spectrum:

    ______________________________________                                        δ ppm =                                                                            6.51, d; 6.72, d; (J = 10Hz) and 4.30,                                        s,: benzodioxane protons                                           =          7.37, s, and 5.16, s = CH.sub.2 --φ                            =          5.76 m : --COCH.sub.2                                              =          3.43, s, : --CH.sub.2 --CO--                                       ______________________________________                                    

EXAMPLE 26: 5-benzyloxy-8-N-methylcarboxamidomethyl-1,4-benzodioxane(XIo) Code Number: 770 379 -First step:2-[(5-benzyloxy-1,4-benzodioxane)yl-5] acetic acid (XXVII) Code Number:770 308

To a solution of 57 g of sodium hydroxide in 1 l of 50% aqueous ethanol,cooled to 0° C., were added 200 g of5-benzyloxy-8-cyanomethyl-1,4-benzodioxane, obtained with the process ofExample 24, then the ethanol was distilled; a solution of hydrochloricacid was added up to acid pH, it was washed with chloroform, acidifiedup to pH=3 and filtered.

Yield: 78%

Melting point: 150° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            6.43, d; 6.65, d, and 4.23, s, :                                              benzodioxane protons                                               =          7.38, s, and 5.08, s, : --CH.sub.2 --φ                         =          3.58, s, : --CH.sub.2 --COO--                                      =          9.20, m. --COOH                                                    ______________________________________                                    

-Second step: 5-benzyloxy-8-N-methylcarboxamidomethyl-1,4-benzodioxane

To a solution of 80 g of 2-[(5-benzyloxy-1,4-benzodioxane)yl-5] aceticacid obtained in the preceding step, in 500 ml of dimethyl formamide,cooled to 0° C., 50 ml of triethylamine were added, then 31 ml of ethylchloroformate. Then a gaseous flow of methylamine was passed and thereaction was checked by chromatography on a thin silica layer. Then itwas poured into iced water, the precipitate formed was filtered andtaken up in chloroform. The organic phase was washed with a dilutedhydrochloric acid solution, the organic phase was evaporated and theresidue recrystallized in ethyl acetate. 70 g of product were obtained.

Yield: 85%

Melting point: 160° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            6.02, d, 6.23, d (J = 9Hz) and 3.82, s, :                                     benzodioxane protons                                               =          6.94, s and 4.63, s, : --CH.sub.2 --φ                          =          3.02, s, : CH.sub.2 --CO--                                         =          2.30, d, (J = 5Hz): --CH.sub.3                                     =          5.12, m, --NH--                                                    ______________________________________                                    

IR spectrum: 3295 and 1640 cm⁻¹ : --CONH--

EXAMPLE 27: 5-benzyloxy-8-hydroxymethyl-1,4-benzodioxane (XIp) CodeNumber: 760 701

A solution of 12.8 g (0.04 mole) of (5-benzyloxy-1,4-benzodioxane)ylethyl carboxylate, obtained according to the method of Example 9, in 50ml of anhydrous tetrahydrofuran was added to a suspension of 1.54 g(0.04 mole) of lithium hydride and aluminum in 150 ml of tetrahydrofuranand left at room temperature for 30 minutes. Then it was hydrolyzed withan aqueous solution of sodium sulfate then with a saturated aqueoussolution of sodium sulfate, filtered, the solvent was evaporated and theresidue recrystallized in benzene. 11 g of product were thus obtained.

Yield: 97%

Melting point: 106° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            6.78, d; 6.51, d; (J = 10Hz) and 4.24, s, :                                   benzodioxane protons                                               =          7.32, s, and 5.12, s; : --CH.sub.2 --φ                         =          4.60 m, and 2.20 m, : --CH.sub.2 OH                                ______________________________________                                    

EXAMPLE 28: 5-benzyloxy-8-cyano-1,4-benzodioxane (XIq) Code Number: 770582

To a solution of 84.5 g of 5-benzyloxy-8-carboxamido-1,4-benzodioxane(XId), code number 770 202, obtained by the method of Example 10, in1000 ml of benzene, were added 80 g of phosphorous pentachloride. Thetemperature rises to 40° C. after 45 minutes, the solvent wasevaporated, and the residue was taken up in toluene, washed with waterand the solvent was evaporated. The residue was recrystallized in ethylacetate.

Yield: 62%

Melting point: 145° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                            6.50, d, 7.01, d, (J = 10Hz) and 4.25,                                        s,: benzodioxane protons                                           =          7.38 s, and 5.05 s, : CH.sub.2 --φ                             ______________________________________                                    

IR spectrum: 2210 cm⁻¹ : band --CN

EXAMPLE 29: 5-benzyloxy-8-ethoxycarbonylmethyl-1,4-benzodioxane (XIr)Code Number: 770 309

To a solution of 72 g of 2-[(5-benzyloxy-1,4-benzodioxane)yl-8] aceticacid, obtained by the method of the first step of Example 26, in 200 mlof ethanol, were added 100 ml of hydrochloric acid in ethanol 7.5 N,then it was brought to reflux for 30 minutes. The solvent wasevaporated, the residue was taken up in chloroform, then it was washedwith a saturated sodium bicarbonate solution, with water, and thesolvent was evaporated. 98% of crystallized product was obtained.

Melting point: 86° C.

NMR spectrum:

    ______________________________________                                        δ ppm =                                                                          6.40, d; 6.61, d (J-10Hz) and 4.18,                                           s,: benzodioxane protons                                             =        7.36, m, and 5.03, s: --CH.sub.2 --φ                             =        3.37, s: --CH.sub.2 --COO                                            =        4.18, q and 1.10, t, (J = 8Hz) : --COO--CH.sub.2 --CH.sub.3          ______________________________________                                    

                                      TABLE II                                    __________________________________________________________________________    HX'Ar'                                                                                                             Melting                                  Code                    Empirical                                                                            Molecular                                                                           Point                                                                              Yield                                                                             IR or NMR spectrum or           Number                                                                             X' Ar'             Formula                                                                              Weight                                                                              °C.                                                                         %   elementary                      __________________________________________________________________________                                                  analysis                        780 387                                                                            S                                                                                 ##STR207##     C.sub.8 H.sub.8 O.sub.2 S                                                            168.210                                                                             oil  85  NMR (CDCL.sub.3) 6.68,m 3                                                     aro- matic protons 4.18,s 4                                                   dioxane protons 3.78, s SH                                                    Elementary analysis             780 382                                                                            S                                                                                 ##STR208##     C.sub.10 H.sub.10 O.sub.3 S                                                          210.246                                                                             78   90   Calc. % Obt.                                                                      C 57.12  57.15                                                                    H 4.79 4.66                                                          Elementary analysis             760 707                                                                            oxy- gen                                                                          ##STR209##     C.sub.10 H.sub.11 NO.sub.4                                                           209.196                                                                             200  92   Calc. % Obt.                                                                      C 57.41 57.32                                                                     H 5.30 5.39                                                                       N 6.70 6.65        780 002                                                                            oxy- gen                                                                          ##STR210##     C.sub.10 H.sub.10 O                                                                  210.18                                                                              oil  100 NMR (CDCl.sub.3) 6.41,s &                                                     4.17,s (6 benzodioxane                                                        protons) δppm   5.55,                                                   s (OH)  2.23, s                                                               (OCOCH.sub.3)                   770 583                                                                            oxy- gen                                                                          ##STR211##     C.sub.9 H.sub.7 NO.sub.3                                                             177.154                                                                             165  95.5                                                                              NMR (CDCl.sub.3) 7.08,d (J                                                    = 10Hz); δppm 6.5,d                                                     (J = 10Hz) & 4.35,s (6                                                        benzodioxane protons)                                                         9.35,s OH                                                                     Elementary analysis             770 523                                                                            oxy- gen                                                                          ##STR212##     C.sub.11 H.sub.13 NO.sub.5                                                           239.22                                                                              123  70   Calc. % Obt.                                                                      C 55.22 55.27                                                                     H 5.48 5.17                                                                       N 5.86 5.95        780 371                                                                            oxy- gen                                                                          ##STR213##     C.sub.12 H.sub.15 O.sub.5                                                            238.232                                                                             125  87                                                                                 ##STR214##                     780 367                                                                            oxy- gen                                                                          ##STR215##     C.sub.13 H.sub.16 O.sub.5                                                            252.288                                                                             156  94  NMR (CDCl.sub.3) 7.4,d (J =                                                   10Hz); δppm 6.5,d (J                                                    = 10Hz) & 4.3,s (6                                                            benzodioxane protons) 6.35                                                    s OH 1.57 s COO+                780 299                                                                            oxy- gen                                                                          ##STR216##     C.sub.14 H.sub.18 O.sub.5                                                            266.284                                                                             45   100 NMR (CDCl.sub.3) 7.38,d (J                                                    = 10Hz); δppm 6.48,d                                                    (J = 10Hz) & 4.22,s (6                                                        benzodioxane protons) 0.75                                                    to 2.0 massive (COOC.sub.5                                                    H.sub.11 n)                     780 331                                                                            oxy- gen                                                                          ##STR217##     C.sub.15 H.sub.18 O.sub.5                                                            278.294                                                                             114  100                                                                                ##STR218##                     770 203                                                                            oxy- gen                                                                          ##STR219##     C.sub.9 H.sub.9 NO.sub.4                                                             195.17                                                                              220  97.5                                                                              NMR (DMSO) 7.45,d (J =                                                        10Hz); δppm 6.5,d (J                                                    = 10Hz) & 4.38,s (6                                                           benzodioxane protons) 7.4,s                                                   CONH.sub.2                      770 829                                                                            oxy- gen                                                                          ##STR220##     C.sub.15 H.sub.19 NO.sub.4                                                           277.310                                                                             182  92                                                                                 ##STR221##                     770 850                                                                            oxy- gen                                                                          ##STR222##     C.sub.15 H.sub.13 NO.sub.4                                                           271.262                                                                             163  100 NMR (DMSO) 7.4,m & 6.45d                                                      δppm (aromatic                                                          protons) 4.35 m (4 dioxane                                                    pro- tons) 9.83 s (OH)          770 543                                                                            oxy- gen                                                                          ##STR223##     C.sub.11 H.sub.13 NO.sub.4                                                           223.222                                                                             190  90  NMR (DMSO) 7.08,d (J =                                                        10Hz); δppm 6.3,d (J                                                    = 10Hz) & 4.24,s (6                                                           benzodioxane protons) 9.3,s                                                   & 8.9 s OH & NH 2.32q (J =                                                    7Hz) & 1.09,d (J = 7Hz) CO                                                    Et                              770 608                                                                            oxy- gen                                                                          ##STR224##     C.sub.12 H.sub.15 NO.sub.4                                                           237.248                                                                             118  94  NMR (DMSO) 7.1,d (J =                                                         10Hz); δppm 6.3,d (J                                                    = 10Hz) & 4.2,s (6                                                            benzodioxane protons) 9.0 s                                                   & 8.8 s OH & NH 2.3 m; 1.4                                                    m & 0.92,t (J = 6Hz)                                                          COC.sub.3 H.sub.7 n             770 599                                                                            oxy- gen                                                                          ##STR225##     C.sub.13 H.sub.17 NO.sub.4                                                           251.284                                                                             80   100 NMR (DMSO) 7.15,d (J =                                                        10Hz); δppm 6.35,d (J                                                   = 10Hz) & 4.2 s (6                                                            benzodioxane protons) 9.0 s                                                   OH & NH 2.35 m; 0.8 to 1.8                                                    massive COC.sub.4 H.sub.9                                                     n                               770 690                                                                            oxy- gen                                                                          ##STR226##     C.sub.12 H.sub.15 NO.sub.4                                                           237.248                                                                             55   100                                                                                ##STR227##                     770 612                                                                            oxy- gen                                                                          ##STR228##     C.sub.13 H.sub.17 NO.sub.4                                                           251.284                                                                             54   90  NMR (DMSO) 7.02,d (J =                                                        10Hz); δppm 6.35,d (J                                                   = 10Hz) & 4.22,s (6                                                           benzodioxane protons) 9.7 s                                                   & 8.2,s OH & NH 1.20,s CO+      770 531                                                                            oxy- gen                                                                          ##STR229##     C.sub.15 H.sub.19 NO.sub.4                                                           277.31                                                                              68   100                                                                                ##STR230##                     770 527                                                                            oxy- gen                                                                          ##STR231##     C.sub.15 H.sub.13 NO.sub.4                                                           271.262                                                                             84   95                                                                                 ##STR232##                     770 305                                                                            oxy- gen                                                                          ##STR233##     C.sub.11 H.sub.14 N.sub.2 O.sub.4                                                    238.238                                                                             170  98  NMR (DMSO) 7.3,d (J =                                                         10Hz); δppm 6.32,d (J                                                   = 10Hz) & 4.25,s (6                                                           benzodioxane protons) 8.7,s                                                   (OH) 7.45,s; 6.55,m, 3.1,m                                                    & 1.05,t (J = 7Hz) NHCONH                                                     Et                              770 481                                                                            oxy- gen                                                                          ##STR234##     C.sub.12 H.sub.16 N.sub.2 O.sub.4                                                    252.264                                                                             186  85  NMR (DMSO) 7.3,d (J =                                                         10Hz); δppm 6.3,d (J                                                    = 10Hz) & 4.21,s (6                                                           benzodioxane protons)                                                         8.83,s (OH) 7.5,s; 6.55,m;                                                    3.05m & 1.1,m NHCONHC.sub.3                                                   H.sub.7 n                       770 628                                                                            oxy- gen                                                                          ##STR235##     C.sub.12 H.sub.16 N.sub.2 O.sub.4                                                    252.264                                                                             189  77                                                                                 ##STR236##                     770 632                                                                            oxy- gen                                                                          ##STR237##     C.sub.18 H.sub.18 N.sub.2 O.sub.4                                                    266.290                                                                             195  98  NMR (DMSO) 7.32,d (J =                                                        10Hz); δppm 6.28,d (J                                                   = 10Hz) & 4.25,s (6                                                           benzodioxane protons) 9.1,s                                                   (OH) 7.42,s; 6.52,s 3.05,m;                                                   1.38,m & 0.9,m NHCONHC.sub.4                                                   H.sub.9 n                      770 709                                                                            oxy- gen                                                                          ##STR238##     C.sub.18 H.sub.18 N.sub.2 O.sub.4                                                    266.290                                                                             199  99  NMR (DMSO) 7.32,d (J =                                                        10Hz); δppm 6.3,d (J                                                    = 10Hz) & 4.23,s (6                                                           benzodioxane protons)                                                         7.4,s; 6.5,s & 1.27,s                                                         NHCONH+                                                                       Elementary analysis             780 221                                                                            oxy- gen                                                                          ##STR239##     C.sub.16 H.sub.16 N.sub.2 O.sub.5                                                    316.304                                                                             232  87   Calc. % Obt.                                                                      C 60.75 60.65                                                                     H 5.10 5.17                                                                       N 8.86 8.61                                                      Elementary analysis             771 231                                                                            oxy- gen                                                                          ##STR240##     C.sub.11 H.sub.14 N.sub.2 O.sub.4                                                    238.238                                                                             176  75   Calc. % Obt.                                                                      C 55.45 55.61                                                                     H 5.92 5.75                                                                       N 11.76 11.84      771 147                                                                            oxy- gen                                                                          ##STR241##     C.sub.13 H.sub.16 N.sub.2 O.sub.5                                                    280.274                                                                             172-4                                                                              83                                                                                 ##STR242##                                                                   Elementary analysis             771 236                                                                            oxy- gen                                                                          ##STR243##     C.sub.11 H.sub.14 N.sub.2 O.sub.4                                                    238.238                                                                             235  70   Calc. (%) Obt.                                                                     C 55.45 55.41                                                                     H 5.92 6.28                                                                       N 11.76                                                                       11.82             770 310                                                                            oxy- gen                                                                          ##STR244##     C.sub.12 H.sub.14 O.sub.5                                                            238.232                                                                             oil  98  NMR (CDCl.sub.3) 6.65,d (J                                                    = 10Hz); δppm 6.40,d                                                    (J = 10Hz) & 4.20,s (6                                                        benzodioxane protons)                                                         7.32,s (OH)4.18,q (J =                                                        6Hz); 3.51,s & 1.12,t (J =                                                    6Hz) CH.sub.2 CO.sub.2 Et       770 384                                                                            oxy- gen                                                                          ##STR245##     C.sub.10 H.sub.11 NO.sub.4                                                           209.196                                                                             190  95  NMR (DMSO) 6.52,d (J =                                                        10Hz); δppm 6.3,d (J                                                    = 10Hz) & 4.18,s (6                                                           benzodioxane protons) 6.65                                                    to 7.2 massive CONH.sub.2                                                     3.20,s - CH.sub.2 CO            770 380                                                                            oxy- gen                                                                          ##STR246##     C.sub.11 H.sub.13 NO.sub.4                                                           223.222                                                                             170- 5                                                                             98  NMR (DMSO) 6.6,d (J =                                                         10Hz); δppm 6.35,d (J                                                   = 10Hz) & 4.22,s (6                                                           benzodioxane protons)                                                         8.15,s & 7.55 m OH & NH                                                       3.3,s CH.sub.2 CO 2.6,d (J                                                    = 5Hz) CONHCH.sub.3                                                           Elementary analysis             780 306                                                                            oxy- gen                                                                          ##STR247##     C.sub.9 H.sub.8 O.sub.4                                                              180.184                                                                             191  100  Calc. (%) Obt.                                                                     C 60.00 60.30                                                                     H 4.48 4.66                                                         Elementary analysis             780 344                                                                            oxy- gen                                                                          ##STR248##     C.sub.9 H.sub.9 NO.sub.4                                                             195.170                                                                             212  100  Calc. (%) Obt.                                                                     C 55.38 55.17                                                                     H 4.65 4.47                                                                       N 7.18 7.10                                                     Elementary analysis             780 407                                                                            oxy- gen                                                                          ##STR249##     C.sub.9 H.sub.10 N.sub.2 O.sub.4                                                     210.186                                                                             236  92.5                                                                               Calc. (%) Obt.                                                                     C 51.43 51.19                                                                     H 4.79 4.65                                                                       N 13.33                                                                       13.40                                                           Elementary analysis             780 239                                                                            oxy- gen                                                                          ##STR250##     C.sub.11 H.sub.12 O.sub.4                                                            208.206                                                                             121  43   Calc. (%) Obt.                                                                     C 63.45 63.54                                                                     H 5.81 5.89           780 391                                                                            oxy- gen                                                                          ##STR251##     C.sub.11 H.sub.13 NO.sub.4                                                           223.222                                                                             177  51  NMR (DMSO) 7.32,d (J =                                                        10Hz); δppm 6.43,d (J                                                   = 10Hz) 4.05,m & 2.05,m (8                                                    benzodioxe- pine protons)                                                     8.15,b & 7.3,b OH & NH                                                        2.05,s COCH.sub.3               780 466                                                                            oxy- gen                                                                          ##STR252##     C.sub.11 H.sub.14 N.sub.2 O.sub.4                                                    238.228                                                                             182  95  NMR (DMSO) 7.5,d (J =                                                         10Hz); δppm 6.45,d (J                                                   = 10Hz) 4.05,m & 2.1m (8                                                      benzodioxepine protons)                                                       8.3,b; 7.63,s & 6.55,m OH &                                                   NHCONH 2.65,d (J = 4Hz)                                                       CH.sub.3                        760 697                                                                            oxy- gen                                                                          ##STR253##     C.sub.11 H.sub.12 O.sub.5                                                            224.206    100 δppm = 7.40; 6.50; d;                                                   (J = 10Hz) & 4.28,s                                                           benzodioxane protons =                                                        6.35m; OH = 4.31,q, &                                                         1.34,t,(J = 8Hz): COOEt IR:                                                   ands at 1710 & 1200                                                           cm.sup.-1 (COOEt)               770 075                                                                            oxy- gen                                                                          ##STR254##     C.sub.10 H.sub.12 N.sub.2 O.sub.4                                                    224.212                                                                             218  85  δppm = 7.30; 6.30;                                                      d,(J = 10Hz); 4.22,s,:                                                        benzodioxane protons =                                                        7.60,s, & 6.43,d (J = 5Hz):                                                   HCONH = 2.60,d,(J = 5Hz):                                                     CH.sub.3                        770 079                                                                            oxy- gen                                                                          ##STR255##     C.sub.15 H.sub.20 N.sub.2 O.sub.4                                                    292.326                                                                             235  90                                                                                 ##STR256##                     770 083                                                                            oxy- gen                                                                          ##STR257##     C.sub.15 H.sub.15 N.sub.2 O.sub.4                                                    286.27                                                                              215  93                                                                                 ##STR258##                     760 702                                                                            oxy- gen                                                                          ##STR259##     C.sub.9 H.sub.11 O.sub.4                                                             182.17                                                                              136  96.5                                                                              δppm = 6.72,6.50,d,(J                                                   = 10Hz); 4.20s:                                                               benzodioxane protons =                                                        4.38,s,: CH.sub.2OH =                                                         5.50,m,: OH                     770 185                                                                             oxy- gen                                                                         ##STR260##     C.sub.10 H.sub.10 NO.sub.3                                                           191.180                                                                             oil  94  δppm = 6.72,6.52d,(J                                                    = 10Hz), 4.23,s,:                                                             benzodioxane protons =                                                        3.45,s,CH.sub.2CN               __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________     ##STR261##                                                                   Code                           Molec-                                                                            Melting                                    Num-                    Empirical                                                                            ular                                                                              Point                                                                              Yield                                                                             IR or NRM spectrum or             ber p R.sub.9 "         Formula                                                                              Weight                                                                            °C.                                                                         %   elementary analysis               __________________________________________________________________________     780 366                                                                          2 COO +          XI.sub.c                                                                         C.sub.20 H.sub.22 O.sub.5                                                            342.376                                                                           90   58  NMR (CDCl.sub.3) δ ppm                                                  = 7.35,d                                                                      (J = 10Hz) 6.48,d(J = 10Hz)                                                   &                                                                             4.35,s (6 benzodioxane                                                        protons) 7.38,s & 5.18,s                                                      -                                                                              ##STR262##                       780 298                                                                           2 COOC.sub.5 H.sub.11 (n)                                                                      XI.sub.c                                                                         C.sub.21 H.sub.24 O.sub.5                                                            356.402                                                                           50   94  NMR (CDCl.sub.3) δ ppm                                                  = 7.35,d                                                                      (J = 10Hz); 6.45,d(J = 10Hz)                                                  &                                                                             4.27,s (6 benzodioxane                                                        protons) 7.38,s & 5.12,s                                                       ##STR263##                                                                   massive COOC.sub.5 H.sub.11                                                   n                                 780 330                                                                           2                                                                                ##STR264##    XI.sub.c                                                                         C.sub.22 H.sub.24 O.sub.5                                                            368.412                                                                           102  58                                                                                 ##STR265##                       770 202                                                                           2 CONH.sub.2     XI.sub.d                                                                         C.sub.16 H.sub.15 NO.sub.4                                                           285.288                                                                           136  92  Elementary analysis                                                                C    H    N                                                              Cal. %                                                                             67.36                                                                              5.30 4.91                                                           Obt. %                                                                             67.13                                                                              5.37 4.76               770 849                                                                           2                                                                                ##STR266##    XI.sub.d                                                                         C.sub.22 H.sub.19 NO.sub.4                                                           361.38                                                                            196  84  NMR (DMSO) δ ppm =                                                      7.0-7.9,  massive; 6.8,d (J =                                                 10Hz)  (11 aromatic protons)                                                  5.1,  s (OCH.sub.2); 4.4,s (4                                                 dio-  xane protons) 8.7,s:                                                    NH                                770 598                                                                           2 NHCOC.sub.4H.sub.9 (n)                                                                       XI.sub.e                                                                         C.sub.20 H.sub.23 NO.sub.4                                                           341.392                                                                           157  72  NMR (CDCl.sub.3) δ ppm                                                  = 7.75,d                                                                      (J = 10Hz); 6.47,d(10Hz) &                                                    4.26,s (6 benzodioxane                                                        protons) 7.38,s & 5.08,s                                                       ##STR267##                                                                   2.0, massive COC.sub.4                                                        H.sub.9 (n)                       770 689                                                                           2                                                                                ##STR268##    XI.sub.e                                                                         C.sub.19 H.sub.21 NO.sub.4                                                           327.366                                                                           155  74                                                                                 ##STR269##                                                                   2.5,m & 1.07,d (J = 6Hz)                                                       ##STR270##                       770 530                                                                           2                                                                                ##STR271##    XI.sub.e                                                                         C.sub.22 H.sub.25 NO.sub.4                                                           367.43                                                                            145  70                                                                                 ##STR272##                                                                   1.2, to 2.4, massive                                                           ##STR273##                       770 526                                                                           2                                                                                ##STR274##    XI.sub.e                                                                         C.sub.22 H.sub.19 NO.sub.4                                                           361.38                                                                            155  96  NMR (CDCl.sub.3) δ ppm                                                  = 7.9,m; 7.4m  & 6.52,d(J =                                                   10Hz) (aromatic  protons)                                                     5.08,s OCH.sub.2  4.22 s                                                      dioxane protons  8.20 s NH        770 607                                                                           2 NHCOC.sub.3 H.sub.7 n                                                                        XI.sub.e                                                                         C.sub.19 H.sub.21 NO.sub.4                                                           327.366                                                                           134.5                                                                              70  NMR (CDCl.sub.3) δ ppm                                                  = 7.75,d (J =                                                                 10Hz) 6.47,d(J =  10Hz) &                                                     4.22,s (6 benzodioxane pro-                                                   tons) 7.35 s & 5.08 s:                                                         ##STR275##                                                                   & 0.98,t(J = 6Hz) COC.sub.3                                                   H.sub.7 n)                        770 074                                                                           2 NHCONHCH.sub.3 XI.sub.f                                                                         C.sub.17 H.sub.18 N.sub.2 O.sub.4                                                    314.330                                                                           220  98  δ ppm = 7.30,d; 7.52,d;                                                 (J =                                                                          10Hz) & 4.20,s: (benzo-                                                       dioxane protons)                                                              = 7.64,s; 7.50,m; NHCONH                                                      = 7.20,s & 5.00,s:                                                             ##STR276##                                                                   = 2.63,d(J = 5Hz): CH.sub.3       780 220                                                                           2                                                                                ##STR277##    XI.sub.f                                                                         C.sub.23 H.sub.22 N.sub. 2 O.sub.5                                                   406.422                                                                           240  89  NMR (DMSO) δ ppm = 7.4                                                  m; 6.7,  m (aromatic protons)                                                 5.0s:  OCH.sub.2 ; 4.3,s                                                      dioxane pro-  ton) 3.7,s:                                                     OCH.sub.3 8.8 s;  8.0 s                                                       NHCONH                            780 406                                                                           1 NHCONHCH.sub.3 XI.sub.f                                                                         C.sub.16 H.sub.16 N.sub.2 O.sub.4                                                    300.304                                                                           200  100 (DMSO) δ ppm = 7.25,d(J                                                 = 10Hz);                                                                      6.55,d(J = 10Hz) & 5.95,s                                                     (4 benzodioxol protons)                                                        ##STR278##                                                                   7.8,s & 6.15, m NHCONH                                                        2.65,d(J = 5Hz) CH.sub.3          780 238                                                                           3 COCH.sub.3     XI.sub.i                                                                         C.sub.18 H.sub.18 O.sub.4                                                            298.324                                                                           78   43  Elementary analysis:                                                                 C     H                                                                Cal. (%)                                                                              72.46                                                                              6.08                                                             Obt. (%)                                                                             72.33 6.15                 780 463                                                                           3 NHCOCH.sub.3   XI.sub.h                                                                         C.sub.18 H.sub.19 NO.sub.4                                                           313.340                                                                           142  52  NMR (DMSO) δ ppm =                                                      7.38,s; 6.66,                                                                 d(J = 10Hz) (aromatic pro-                                                    tons 5.0 OCH.sub.2 4.05,m &                                                    ##STR279##                                                                   9.1,s NH                          780 465                                                                           3 NHCONHCH.sub.3 XI.sub.f                                                                         C.sub.18 H.sub.20 N.sub.2 O.sub.4                                                    328.346                                                                           140  78  Elementary analysis                                                                C    H    N                                                              Cal. (%)                                                                           65.84                                                                              6.14 8.53                                                           Obt. (%)                                                                           65.54                                                                              6.10 8.23               770 611                                                                           2 NHCO +         XI.sub.e                                                                         C.sub.20 H.sub.23 NO.sub.4                                                           341.392                                                                           113  73  NMR (CDCl.sub.3) δ ppm                                                  = 7.8,d(J =                                                                   10Hz) 6.5 d(J = 10Hz) & 4.3                                                   s (6 benzodioxane protons)                                                     ##STR280##                                                                   1.3,s CO +                        770 480                                                                           2 NHCONHC.sub.3 H.sub.7 (n)                                                                    XI.sub.f                                                                         C.sub.19 H.sub.22 N.sub.2 O.sub.4                                                    342.382                                                                           180  75  Elementary analysis                                                                C    H    N                                                              Cal. (%)                                                                           66.65                                                                              6.48 8.18                                                           Obt. (%)                                                                           66.28                                                                              6.49 8.27               770 627                                                                           2                                                                                ##STR281##    XI.sub.f                                                                         C.sub.19 H.sub.22 N.sub.2 O.sub.4                                                    342.382                                                                           182-4                                                                              80                                                                                 ##STR282##                                                                   3.8 m; 1.1 d (J = 7Hz)                                                         ##STR283##                       770 631                                                                           2 NHCONHC.sub.4 H.sub.9 (n)                                                                    XI.sub.f                                                                         C.sub.20 H.sub.24 N.sub.2 O.sub.4                                                    356.408                                                                           175-8                                                                              84  NMR(DMSO) δppm = 7.5,m;                                                 6.50                                                                          d(J = 10Hz) aromatic pro-                                                     tons) 5.0,s: OCH.sub.2 4.35,                                                  s: dioxane protons 3.1,m;                                                     0.8-1.6, massive C.sub.4                                                      H.sub.9 (n)                                                                   7.7,s; 6.7 m NHCONH               770 708                                                                           2 NHCONH +       XI.sub.f                                                                         C.sub.20 H.sub.24 N.sub.2 O.sub.4                                                    356.408                                                                           174  98  NMR(DMSO) δppm =                                                        7.3,d(J = 10                                                                  Hz); 6.35,d(J = 10Hz) &                                                       4.35,s                                                                        (6 benzodioxane protons)                                                       ##STR284##                                                                   7.62,s; 6.65,s; 1.3,s                                                         NHCONH +                          770 078                                                                           2                                                                                ##STR285##    XI.sub.f                                                                         C.sub.22 H.sub.26 N.sub.2 O.sub.4                                                    382.444                                                                           225  94                                                                                 ##STR286##                       770 082                                                                           2                                                                                ##STR287##    XI.sub.f                                                                         C.sub.22 H.sub.20 N.sub.2 O.sub.4                                                    376.39                                                                            218  95  NMR (DMSO) δppm =                                                       7.4,m; 6.60, d(J = 10Hz)                                                      aromatic protons 5.01,s:                                                      OCH.sub.2 ; 4.32,s                                                            dioxane protons 9.1,s;                                                        8.0 s NHCONH                      __________________________________________________________________________

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A compound having theformula ##STR288## wherein n is 1, 2 or 3, and (A) when n is 2, R₉ isselected from the group consisting of methoxy, acetyl, hydroxy, acetoxy,alkoxycarbonyl in which the alkyl has 2 to 5 carbon atoms,cyclohexyloxycarbonyl, carboxamido, N-methylcarboxamido,N-cyclohexylcarboxamido, N-phenylcarboxamido, alkanoylamino in which thealkyl has 2 to 5 carbon atoms, cyclohexylcarbonylamino, benzoylamino,N-alkylcarbamoylamino in which the alkyl has 1 to 5 carbon atoms,N-cyclohexylcarbamoylamino, N-phenylcarbamoylamino,N-paramethoxyphenylcarbamoylamino, ethoxycarbonylamino,N,N'-dimethylcarbamoylamino, methylamino, morpholinocarbonylamino,N,N-dimethylcarbamoylamino, carboxamidomethyl,N-methylcarboxamidomethyl, hydroxycarbonylmethyl, cyano, ethyl acetate,carboxy, amino, hydroxymethyl, cyanomethyl, chloromethyl and acetamido,and(B) when n is 1 or 3, R₉ is selected from the group consisting ofacetyl, amino, acetamido and acetyl oxime.
 2. A compound according toclaim 1 in which the combination of parameters n and R₉ is as defined in(A).
 3. A compound according to claim 1 in which the combination ofparameters n and R₉ is as defined in (B).
 4. A compound according toclaim 1 having the formula ##STR289##
 5. A compound according to claim 1having the formula ##STR290##
 6. A compound according to claim 1 havingthe formula ##STR291##
 7. A compound according to claim 1 having theformula ##STR292##
 8. A compound according to claim 1 having the formula##STR293##